Anti-sars-cov-2 antibodies and uses thereof

ABSTRACT

Provided herein are modified anti-SARS-COV-2 antibodies or antigen binding fragments thereof having extended half life and optimized immune activities. Disclosed herein is also directed to pharmaceutical compositions comprising the same and a method for treating or preventing a disease in human patients that is caused by or related to the infection of SARS-COV-2.

CROSS REFERENCE

This application is a continuation application of U.S. application Ser.No. 16/953,304, and claims the priorities of Foreign Applications No.CN202010203065.1, filed on Mar. 20, 2020; PCT/CN2020/080532, filed Mar.21, 2020; PCT/CN2020/084097, filed on Apr. 10, 2020; PCT/CN2020/084805,filed on Apr. 14, 2020; and PCT/CN2020/108718, filed on Aug. 12, 2020;which are hereby incorporated by reference.

FIELD OF THE DISCLOSURE

The present disclosure generally relates to novel anti-SARS-COV-2antibodies, pharmaceutical composition containing the same and the usethereof.

BACKGROUND

The recent outbreak of the new coronavirus, SARS-CoV-2 poses a seriousglobal health emergency. SARS-CoV-2 is a positive-sense single-strandedRNA (+ssRNA) virus which belongs to the betacoronavirus family andshares substantial genetic and functional similarity with otherpathogenic human betacoronaviruses, including Severe Acute RespiratorySyndrome Coronavirus (SARS-CoV, also called SARS-CoV-1) and Middle EastRespiratory Syndrome Coronavirus (MERS-CoV). Like other coronaviruses,SARS-CoV-2 has four structural proteins, known as the S (spike), E(envelope), M (membrane), and N (nucleocapsid) proteins; the S, E, and Mproteins together create the viral envelope; inside the envelope is theN protein bounding to the RNA genome (˜30 kb) in a continuousbeads-on-a-string type conformation.

The spike protein is the protein responsible for allowing the SARS-CoV-2virus to attach to the membrane of a host cell, the receptor bindingdomain (RBD) of the spike protein of SARS-CoV-2 recognizes and attachesto the angiotensin-converting enzyme 2 (ACE2) receptor of host cells touse them as a mechanism of cell entry. The overall ACE2-bindingmechanism is virtually the same between SARS-CoV-2 RBD and SARS-CoV RBD,indicating convergent ACE2-binding evolution between these two viruses.This suggests that disruption of the RBD and ACE2 interaction wouldblock the entry of SARS-CoV-2 into the target cell. Indeed, a few suchdisruptive agents targeted to ACE2 have been shown to inhibit SARS-CoVinfection. However, given the important physiological roles of ACE2 invivo, these agents may have undesired side effects. Anti-RBD antibodies,on the other hand, are therefore more favorable. Furthermore,SARS-CoV-RBD or MERS-CoV RBD-based vaccine studies in experimentalanimals have also shown strong polyclonal antibody responses thatinhibit viral entry. Such critical proof-of-concept findings indicatethat anti-RBD antibodies might effectively block SARS-CoV-2 entry.

No SARS-CoV-2-specific treatments or vaccine are currently available,and the currently existing detective measures for SARS-CoV-2 infectionare time-consuming and insensitive. Hence, there is an urgent need fornovel anti-SARS-CoV-2 antibodies.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present disclosure is directed to a modified antibodyor an antigen-binding fragment thereof comprising at least anantigen-binding domain having an antigen-binding affinity and acovalently linked modified human IgG constant domain, wherein theantigen-binding affinity comprises SARS-CoV-2 binding affinity, theantigen-binding affinity comprises at least 50% less or non-detectablebinding affinity to SARS-CoV or MERS-CoV compared to the SARS-CoV-2binding affinity, and wherein the modified human IgG constant domaincomprises a substitution with tyrosine at amino acid residue 252, asubstitution with threonine at amino acid residue 254, and asubstitution with glutamic acid at amino acid residue 256, numberedaccording to the EU index as in Kabat, the modified antibody has anincreased affinity for FcRn compared to the affinity to FcRn of anantibody having a wild type human IgG constant domain.

In another aspect, the present disclosure is directed to apharmaceutical composition comprising at least one the modified antibodyor an antigen-binding fragment thereof of disclosed herein, at least onenucleic acid encoding the modified antibody or the antigen-bindingfragment thereof, or a combination thereof, and one or morepharmaceutically acceptable carriers.

In another aspect, the present disclosure is directed to a method fortreating or preventing a disease in a subject in need thereof, themethod comprising administering an effective dosage of any of thepharmaceutical composition of disclosed herein to the subject;

wherein the pharmaceutical composition is configured to be administeredto the subject to maintain a plasma concentration of the modifiedantibody or an antigen-binding fragment thereof in a therapeuticeffective range of from 10 μg/mL to 3500 μg/mL for a time period in arange of from 1 day to 12 months after administering the pharmaceuticalcomposition; and

wherein the subject is infected with, exhibiting one or more symptoms ofbeing infected with, or at risk of being infected with the SARS-CoV-2.

In another aspect, the present disclosure provides an isolated orrecombinant antibody or an antigen-binding fragment thereof, which iscapable of specifically binding to SARS-CoV-2, and exhibiting at least50% less binding or non-detectable binding to SARS-CoV or MERS-CoV.

In another aspect, the present disclosure provides an isolated orrecombinant antibody or an antigen-binding fragment thereof, having oneor more features selected from the group consisting of: a) capable ofspecifically binding to spike protein of SARS-CoV-2 and exhibiting atleast 50% less binding to spike protein of SARS-CoV or spike protein ofMERS-CoV; b) capable of specifically binding to receptor-binding domain(RBD) of the spike protein of SARS-CoV-2 comprising the amino acidsequence of SEQ ID NO: 128; c) exhibiting binding to RBD of spikeprotein of SARS-CoV comprising the amino acid sequence of SEQ ID NO: 124at a level that is non-detectable or that is no more than 50% of thebinding to the RBD of spike protein of SARS-CoV-2; d) exhibiting bindingto RBD of spike protein of MERS-CoV comprising the amino acid sequenceof SEQ ID NO: 126 at a level that is non-detectable or that is no morethan 50% of the binding to RBD of the spike protein of SARS-CoV-2; e)capable of binding to the RBD of spike protein of SARS-CoV-2 at a K_(d)value of no more than 1×10⁻⁷M as measured by Surface Plasmon resonance(SPR); f) exhibiting binding to the RBD of spike protein of SARS-CoV orthe RBD of spike protein of MERS-CoV at a K_(d) value of at least 1×10⁻⁶M as measured by SPR; g) capable of exhibiting at least 30% competitionat with 2 μM angiotensin converting enzyme 2 (ACE2) receptor, forbinding to the RBD of spike protein of SARS-CoV-2 immobilized at aresonance units (RU) of 250, as measured by SPR; h) capable of bindingto the RBD of spike protein of SARS-CoV-2 at an neutralizing activity atan IC₅₀ value of no more than 100 μg/ml (for example, no more than 50μg/ml, no more than 40 μg/ml, no more than 30 μg/ml, no more than 25μg/ml, no more than 20 μg/ml, no more than 15 μg/ml, no more than 10μg/ml, no more than 8 μg/ml, no more than 6 μg/ml, no more than 4 μg/ml,no more than 2 μg/ml, or no more than 1 μg/ml), as measured bypseudovirus neutralization assay, and 1) capable of binding to the RBDof spike protein of SARS-CoV-2 at an neutralizing activity at an IC₅₀value of no more than 1 μg/ml (for example, no more than 50 ng/ml, nomore than 40 ng/ml, no more than 30 ng/ml, no more than 25 ng/ml, nomore than 20 ng/ml, no more than 15 ng/ml, no more than 10 ng/ml, nomore than 8 ng/ml, no more than 6 ng/ml, no more than 4 ng/ml, no morethan 2 ng/ml, or no more than 1 ng/ml), as measured by live virusneutralization assay using focus reduction neutralization test (FRNT)method.

In yet another aspect, the present disclosure provides an isolated orrecombinant antibody or an antigen-binding fragment thereof capable ofspecifically binding to RBD of spike protein of SARS-CoV-2.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 21, SEQ ID NO: 22, and SEQ ID NO: 23.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 31, SEQ ID NO: 32, and SEQ ID NO: 33.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 41, SEQ ID NO: 42, and SEQ ID NO: 43.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 51, SEQ ID NO: 52, and SEQ ID NO: 53.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 65, SEQ ID NO: 66, and SEQ ID NO: 67.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 75, SEQ ID NO: 76, and SEQ ID NO: 77.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 85, SEQ ID NO: 86, and SEQ ID NO: 87.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 95, SEQ ID NO: 96, and SEQ ID NO: 97.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 105, SEQ ID NO: 106, and SEQ ID NO: 107.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 136, SEQ ID NO: 137, and SEQ ID NO: 138.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 146, SEQ ID NO: 147, and SEQ ID NO: 148.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 156, SEQ ID NO: 157, and SEQ ID NO: 158.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 166, SEQ ID NO: 167, and SEQ ID NO: 168.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 176, SEQ ID NO: 177, and SEQ ID NO: 178.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 186, SEQ ID NO: 187, and SEQ ID NO: 188.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 196, SEQ ID NO: 197, and SEQ ID NO: 198.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 206, SEQ ID NO: 207, and SEQ ID NO: 208.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 216, SEQ ID NO: 217, and SEQ ID NO: 218.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 226, SEQ ID NO: 227, and SEQ ID NO: 228.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 236, SEQ ID NO: 237, and SEQ ID NO: 238.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 246, SEQ ID NO: 247, and SEQ ID NO: 248.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 256, SEQ ID NO: 257, and SEQ ID NO: 258.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 266, SEQ ID NO: 267, and SEQ ID NO: 268.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 276, SEQ ID NO: 277, and SEQ ID NO: 278.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 286, SEQ ID NO: 287, and SEQ ID NO: 288.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 296, SEQ ID NO: 297, and SEQ ID NO: 298.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 306, SEQ ID NO: 307, and SEQ ID NO: 308.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 316, SEQ ID NO: 317, and SEQ ID NO: 318.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 326, SEQ ID NO: 327, and SEQ ID NO: 328.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 336, SEQ ID NO: 337, and SEQ ID NO: 338.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 346, SEQ ID NO: 347, and SEQ ID NO: 348.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 266, SEQ ID NO: 267, and SEQ ID NO: 268.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 356, SEQ ID NO: 357, and SEQ ID NO: 358.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 366, SEQ ID NO: 367, and SEQ ID NO: 368.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 376, SEQ ID NO: 377, and SEQ ID NO: 378.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 386, SEQ ID NO: 387, and SEQ ID NO: 388.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 396, SEQ ID NO: 397, and SEQ ID NO: 398.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 416, SEQ ID NO: 417, and SEQ ID NO: 418.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 heavy chain CDR sequencesselected from SEQ ID NO: 426, SEQ ID NO: 427, and SEQ ID NO: 428.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 24, SEQ ID NO: 25 and SEQ ID NO: 26.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 34, SEQ ID NO: 35 and SEQ ID NO: 36.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 44, SEQ ID NO: 45 and SEQ ID NO: 46.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 54, SEQ ID NO: 55 and SEQ ID NO: 56.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 68, SEQ ID NO: 69, and SEQ ID NO: 70.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 78, SEQ ID NO: 79, and SEQ ID NO: 80.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 88, SEQ ID NO: 89, and SEQ ID NO: 90.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 98, SEQ ID NO: 99, and SEQ ID NO: 100.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 108, SEQ ID NO: 109, and SEQ ID NO: 110.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 139, SEQ ID NO: 140, and SEQ ID NO: 141.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 149, SEQ ID NO: 150, and SEQ ID NO: 151.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 159, SEQ ID NO: 160, and SEQ ID NO: 161.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 169, SEQ ID NO: 170, and SEQ ID NO: 171.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 179, SEQ ID NO: 180, and SEQ ID NO: 181.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 189, SEQ ID NO: 190, and SEQ ID NO: 191.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 199, SEQ ID NO: 200, and SEQ ID NO: 201.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 209, SEQ ID NO: 210, and SEQ ID NO: 211.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 219, SEQ ID NO: 220, and SEQ ID NO: 221.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 229, SEQ ID NO: 230, and SEQ ID NO: 231.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 239, SEQ ID NO: 240, and SEQ ID NO: 241.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 249, SEQ ID NO: 250, and SEQ ID NO: 251.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 259, SEQ ID NO: 260, and SEQ ID NO: 261.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 269, SEQ ID NO: 270, and SEQ ID NO: 271.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 279, SEQ ID NO: 280, and SEQ ID NO: 281.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 289, SEQ ID NO: 290, and SEQ ID NO: 291.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 299, SEQ ID NO: 300, and SEQ ID NO: 301.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 309, SEQ ID NO: 310, and SEQ ID NO: 311.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 319, SEQ ID NO: 320, and SEQ ID NO: 321.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 329, SEQ ID NO: 330, and SEQ ID NO: 331.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 339, SEQ ID NO: 340, and SEQ ID NO: 341.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 349, SEQ ID NO: 350, and SEQ ID NO: 351.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 359, SEQ ID NO: 360, and SEQ ID NO: 361.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 369, SEQ ID NO: 370, and SEQ ID NO: 371.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 379, SEQ ID NO: 380, and SEQ ID NO: 381.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 389, SEQ ID NO: 390, and SEQ ID NO: 391.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 399, SEQ ID NO: 400, and SEQ ID NO: 401.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 409, SEQ ID NO: 410, and SEQ ID NO: 411.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 419, SEQ ID NO: 420, and SEQ ID NO: 421.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises 1, 2, or 3 light chain CDR sequencesselected from SEQ ID NO: 429, SEQ ID NO: 430, and SEQ ID NO: 431.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a heavy chain CDR1 (HCDR1) comprising thesequence of SEQ ID NO: 1, a heavy chain CDR2 (HCDR2) comprising thesequence of SEQ ID NO: 2, a heavy chain CDR3 (HCDR3) comprising thesequence of SEQ ID NO: 3; a light chain CDR1 (LCDR1) comprising thesequence of SEQ ID NO: 4, a light chain CDR2 (LCDR2) comprising thesequence of SEQ ID NO: 5, and a light chain CDR3 (LCDR3) comprising thesequence of SEQ ID NO: 6.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 11, a HCDR2 comprising the sequence of SEQ ID NO: 12, a HCDR3comprising the sequence of SEQ ID NO: 13, a LCDR1 comprising thesequence of SEQ ID NO: 14, a LCDR2 comprising the sequence of SEQ ID NO:15, and a LCDR3 comprising the sequence of SEQ ID NO: 16.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 21, a HCDR2 comprising the sequence of SEQ ID NO: 22, a HCDR3comprising the sequence of SEQ ID NO: 23, a LCDR1 comprising thesequence of SEQ ID NO: 24, a LCDR2 comprising the sequence of SEQ ID NO:25, and a LCDR3 comprising the sequence of SEQ ID NO: 26.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 31, a HCDR2 comprising the sequence of SEQ ID NO: 32, a HCDR3comprising the sequence of SEQ ID NO: 33, a LCDR1 comprising thesequence of SEQ ID NO: 34, a LCDR2 comprising the sequence of SEQ ID NO:35, and a LCDR3 comprising the sequence of SEQ ID NO: 36.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 41, a HCDR2 comprising the sequence of SEQ ID NO: 42, a HCDR3comprising the sequence of SEQ ID NO: 43, a LCDR1 comprising thesequence of SEQ ID NO: 44, a LCDR2 comprising the sequence of SEQ ID NO:45, and a LCDR3 comprising the sequence of SEQ ID NO: 46.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 51, a HCDR2 comprising the sequence of SEQ ID NO: 52, a HCDR3comprising the sequence of SEQ ID NO: 53, a LCDR1 comprising thesequence of SEQ ID NO: 54, a LCDR2 comprising the sequence of SEQ ID NO:55, and a LCDR3 comprising the sequence of SEQ ID NO: 56.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 65, a HCDR2 comprising the sequence of SEQ ID NO: 66, a HCDR3comprising the sequence of SEQ ID NO: 67, a LCDR1 comprising thesequence of SEQ ID NO: 68, a LCDR2 comprising the sequence of SEQ ID NO:69, and a LCDR3 comprising the sequence of SEQ ID NO: 70.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 75, a HCDR2 comprising the sequence of SEQ ID NO: 76, a HCDR3comprising the sequence of SEQ ID NO: 77, a LCDR1 comprising thesequence of SEQ ID NO: 78, a LCDR2 comprising the sequence of SEQ ID NO:79, and a LCDR3 comprising the sequence of SEQ ID NO: 80.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 85, a HCDR2 comprising the sequence of SEQ ID NO: 86, a HCDR3comprising the sequence of SEQ ID NO: 87, a LCDR1 comprising thesequence of SEQ ID NO: 88, a LCDR2 comprising the sequence of SEQ ID NO:89, and a LCDR3 comprising the sequence of SEQ ID NO: 90.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 95, a HCDR2 comprising the sequence of SEQ ID NO: 96, a HCDR3comprising the sequence of SEQ ID NO: 97, a LCDR1 comprising thesequence of SEQ ID NO: 98, a LCDR2 comprising the sequence of SEQ ID NO:99, and a LCDR3 comprising the sequence of SEQ ID NO: 100.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 105, a HCDR2 comprising the sequence of SEQ ID NO: 106, a HCDR3comprising the sequence of SEQ ID NO: 107, a LCDR1 comprising thesequence of SEQ ID NO: 108, a LCDR2 comprising the sequence of SEQ IDNO: 109, and a LCDR3 comprising the sequence of SEQ ID NO: 110.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 136, a HCDR2 comprising the sequence of SEQ ID NO: 137, a HCDR3comprising the sequence of SEQ ID NO: 138, a LCDR1 comprising thesequence of SEQ ID NO: 139, a LCDR2 comprising the sequence of SEQ IDNO: 140, and a LCDR3 comprising the sequence of SEQ ID NO: 141.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 146, a HCDR2 comprising the sequence of SEQ ID NO: 147, a HCDR3comprising the sequence of SEQ ID NO: 148, a LCDR1 comprising thesequence of SEQ ID NO: 149, a LCDR2 comprising the sequence of SEQ IDNO: 150, and a LCDR3 comprising the sequence of SEQ ID NO: 151.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 156, a HCDR2 comprising the sequence of SEQ ID NO: 157, a HCDR3comprising the sequence of SEQ ID NO: 158, a LCDR1 comprising thesequence of SEQ ID NO: 159, a LCDR2 comprising the sequence of SEQ IDNO: 160, and a LCDR3 comprising the sequence of SEQ ID NO: 161.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 166, a HCDR2 comprising the sequence of SEQ ID NO: 167, a HCDR3comprising the sequence of SEQ ID NO: 168, a LCDR1 comprising thesequence of SEQ ID NO: 169, a LCDR2 comprising the sequence of SEQ IDNO: 170, and a LCDR3 comprising the sequence of SEQ ID NO: 171.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 176, a HCDR2 comprising the sequence of SEQ ID NO: 177, a HCDR3comprising the sequence of SEQ ID NO: 178, a LCDR1 comprising thesequence of SEQ ID NO: 179, a LCDR2 comprising the sequence of SEQ IDNO: 180, and a LCDR3 comprising the sequence of SEQ ID NO: 181.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 186, a HCDR2 comprising the sequence of SEQ ID NO: 187, a HCDR3comprising the sequence of SEQ ID NO: 188, a LCDR1 comprising thesequence of SEQ ID NO: 189, a LCDR2 comprising the sequence of SEQ IDNO: 190, and a LCDR3 comprising the sequence of SEQ ID NO: 191.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 196, a HCDR2 comprising the sequence of SEQ ID NO: 197, a HCDR3comprising the sequence of SEQ ID NO: 198, a LCDR1 comprising thesequence of SEQ ID NO: 199, a LCDR2 comprising the sequence of SEQ IDNO: 200, and a LCDR3 comprising the sequence of SEQ ID NO: 201.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 206, a HCDR2 comprising the sequence of SEQ ID NO: 207, a HCDR3comprising the sequence of SEQ ID NO: 208, a LCDR1 comprising thesequence of SEQ ID NO: 209, a LCDR2 comprising the sequence of SEQ IDNO: 210, and a LCDR3 comprising the sequence of SEQ ID NO: 211.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 216, a HCDR2 comprising the sequence of SEQ ID NO: 217, a HCDR3comprising the sequence of SEQ ID NO: 218, a LCDR1 comprising thesequence of SEQ ID NO: 219, a LCDR2 comprising the sequence of SEQ IDNO: 220, and a LCDR3 comprising the sequence of SEQ ID NO: 221.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 226, a HCDR2 comprising the sequence of SEQ ID NO: 227, a HCDR3comprising the sequence of SEQ ID NO: 228, a LCDR1 comprising thesequence of SEQ ID NO: 229, a LCDR2 comprising the sequence of SEQ IDNO: 230, and a LCDR3 comprising the sequence of SEQ ID NO: 231.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 236, a HCDR2 comprising the sequence of SEQ ID NO: 237, a HCDR3comprising the sequence of SEQ ID NO: 238, a LCDR1 comprising thesequence of SEQ ID NO: 239, a LCDR2 comprising the sequence of SEQ IDNO: 240, and a LCDR3 comprising the sequence of SEQ ID NO: 241.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 246, a HCDR2 comprising the sequence of SEQ ID NO: 247, a HCDR3comprising the sequence of SEQ ID NO: 248, a LCDR1 comprising thesequence of SEQ ID NO: 249, a LCDR2 comprising the sequence of SEQ IDNO: 250, and a LCDR3 comprising the sequence of SEQ ID NO: 251.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 256, a HCDR2 comprising the sequence of SEQ ID NO: 257, a HCDR3comprising the sequence of SEQ ID NO: 258, a LCDR1 comprising thesequence of SEQ ID NO: 259, a LCDR2 comprising the sequence of SEQ IDNO: 260, and a LCDR3 comprising the sequence of SEQ ID NO: 261.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 266, a HCDR2 comprising the sequence of SEQ ID NO: 267, a HCDR3comprising the sequence of SEQ ID NO: 268, a LCDR1 comprising thesequence of SEQ ID NO: 269, a LCDR2 comprising the sequence of SEQ IDNO: 270, and a LCDR3 comprising the sequence of SEQ ID NO: 271.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 276, a HCDR2 comprising the sequence of SEQ ID NO: 277, a HCDR3comprising the sequence of SEQ ID NO: 278, a LCDR1 comprising thesequence of SEQ ID NO: 279, a LCDR2 comprising the sequence of SEQ IDNO: 280, and a LCDR3 comprising the sequence of SEQ ID NO: 281.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 286, a HCDR2 comprising the sequence of SEQ ID NO: 287, a HCDR3comprising the sequence of SEQ ID NO: 288, a LCDR1 comprising thesequence of SEQ ID NO: 289, a LCDR2 comprising the sequence of SEQ IDNO: 290, and a LCDR3 comprising the sequence of SEQ ID NO: 291.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 296, a HCDR2 comprising the sequence of SEQ ID NO: 297, a HCDR3comprising the sequence of SEQ ID NO: 298, a LCDR1 comprising thesequence of SEQ ID NO: 299, a LCDR2 comprising the sequence of SEQ IDNO: 300, and a LCDR3 comprising the sequence of SEQ ID NO: 301.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 306, a HCDR2 comprising the sequence of SEQ ID NO: 307, a HCDR3comprising the sequence of SEQ ID NO: 308, a LCDR1 comprising thesequence of SEQ ID NO: 309, a LCDR2 comprising the sequence of SEQ IDNO: 310, and a LCDR3 comprising the sequence of SEQ ID NO: 311.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 316, a HCDR2 comprising the sequence of SEQ ID NO: 317, a HCDR3comprising the sequence of SEQ ID NO: 318, a LCDR1 comprising thesequence of SEQ ID NO: 319, a LCDR2 comprising the sequence of SEQ IDNO: 320, and a LCDR3 comprising the sequence of SEQ ID NO: 321.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 326, a HCDR2 comprising the sequence of SEQ ID NO: 327, a HCDR3comprising the sequence of SEQ ID NO: 328, a LCDR1 comprising thesequence of SEQ ID NO: 329, a LCDR2 comprising the sequence of SEQ IDNO: 330, and a LCDR3 comprising the sequence of SEQ ID NO: 331.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 336, a HCDR2 comprising the sequence of SEQ ID NO: 337, a HCDR3comprising the sequence of SEQ ID NO: 338, a LCDR1 comprising thesequence of SEQ ID NO: 339, a LCDR2 comprising the sequence of SEQ IDNO: 340, and a LCDR3 comprising the sequence of SEQ ID NO: 341.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 346, a HCDR2 comprising the sequence of SEQ ID NO: 347, a HCDR3comprising the sequence of SEQ ID NO: 348, a LCDR1 comprising thesequence of SEQ ID NO: 349, a LCDR2 comprising the sequence of SEQ IDNO: 350, and a LCDR3 comprising the sequence of SEQ ID NO: 351.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 356, a HCDR2 comprising the sequence of SEQ ID NO: 357, a HCDR3comprising the sequence of SEQ ID NO: 358, a LCDR1 comprising thesequence of SEQ ID NO: 359, a LCDR2 comprising the sequence of SEQ IDNO: 360, and a LCDR3 comprising the sequence of SEQ ID NO: 361.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 366, a HCDR2 comprising the sequence of SEQ ID NO: 367, a HCDR3comprising the sequence of SEQ ID NO: 368, a LCDR1 comprising thesequence of SEQ ID NO: 369, a LCDR2 comprising the sequence of SEQ IDNO: 370, and a LCDR3 comprising the sequence of SEQ ID NO: 371.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 376, a HCDR2 comprising the sequence of SEQ ID NO: 377, a HCDR3comprising the sequence of SEQ ID NO: 378, a LCDR1 comprising thesequence of SEQ ID NO: 379, a LCDR2 comprising the sequence of SEQ IDNO: 380, and a LCDR3 comprising the sequence of SEQ ID NO: 381.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 386, a HCDR2 comprising the sequence of SEQ ID NO: 387, a HCDR3comprising the sequence of SEQ ID NO: 388, a LCDR1 comprising thesequence of SEQ ID NO: 389, a LCDR2 comprising the sequence of SEQ IDNO: 390, and a LCDR3 comprising the sequence of SEQ ID NO: 391.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 396, a HCDR2 comprising the sequence of SEQ ID NO: 397, a HCDR3comprising the sequence of SEQ ID NO: 398, a LCDR1 comprising thesequence of SEQ ID NO: 399, a LCDR2 comprising the sequence of SEQ IDNO: 400, and a LCDR3 comprising the sequence of SEQ ID NO: 401.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 406, a HCDR2 comprising the sequence of SEQ ID NO: 407, a HCDR3comprising the sequence of SEQ ID NO: 408, a LCDR1 comprising thesequence of SEQ ID NO: 409, a LCDR2 comprising the sequence of SEQ IDNO: 410, and a LCDR3 comprising the sequence of SEQ ID NO: 411.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 416, a HCDR2 comprising the sequence of SEQ ID NO: 417, a HCDR3comprising the sequence of SEQ ID NO: 418, a LCDR1 comprising thesequence of SEQ ID NO: 419, a LCDR2 comprising the sequence of SEQ IDNO: 420, and a LCDR3 comprising the sequence of SEQ ID NO: 421.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a HCDR1 comprising the sequence of SEQ IDNO: 426, a HCDR2 comprising the sequence of SEQ ID NO: 427, a HCDR3comprising the sequence of SEQ ID NO: 428, a LCDR1 comprising thesequence of SEQ ID NO: 429, a LCDR2 comprising the sequence of SEQ IDNO: 430, and a LCDR3 comprising the sequence of SEQ ID NO: 431.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a heavy chain variable region comprises asequence selected from the group consisting of SEQ ID NO: 7, 17, 27, 37,47, 57, 61, 71, 81, 91, 101, 111, 142, 152, 162, 172, 182, 192, 202,212, 222, 232, 242, 252, 262, 272, 282, 292, 302, 312, 322, 332, 342,352, 362, 372, 382, 392, 402, 412, 422 and 432, or a homologous sequencethereof having at least 80% sequence identity.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a light chain variable region comprises asequence selected from the group consisting of SEQ ID NO: 8, 18, 28, 38,48, 58, 62, 72, 82, 92, 102, 112, 143, 153, 163, 173, 183, 193, 203,213, 223, 233, 243, 253, 263, 273, 283, 293, 303, 313, 323, 333, 343,353, 363, 373, 383, 393, 403, 413, 423 and 433, or a homologous sequencethereof having at least 80% sequence identity.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises a pair of heavy chain variable region andlight chain variable region sequences selected from the group consistingof: SEQ ID NOs: 7/8, 17/18, 27/28, 37/38, 47/48, 57/58, 61/62, 71/72,81/82, 91/92, 101/102, 111/112, and 142/143, 152/153, 162/163, 172/173,182/183, 192/193, 202/203, 212/213, 222/223, 232/233, 242/243, 252/253,262/263, 272/273, 282/283, 292/293, 302/303, 312/313, 322/323, 332/333,342/343, 352/353, 362/363, 372/373, 382/383, 392/393, 402/403, 412/413,422/423 and 432/433, or a pair of homologous sequences thereof having atleast 80% sequence identity yet retaining specific binding affinity toRBD of spike protein of SARS-CoV-2.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure further comprises an immunoglobulin constant region.In some embodiments, the immunoglobulin constant region is a constantregion of human immunoglobulin. In some embodiments, the immunoglobulinconstant region is a constant region of human IgG. In some embodiments,the antibody or antigen binding fragment of the present disclosurecomprises a heavy chain constant region of human IgG1, IgG2, IgG3, IgG4,IgA1, IgA2 or IgM. In some embodiments, the antibody or antigen bindingfragment of the present disclosure comprises a heavy chain constantregion of human IgG1. In some embodiments, the antibody or antigenbinding fragment of the present disclosure comprises a constant regionof human immunoglobulin kappa 1 light chain. In some embodiments, theantibody or antigen binding fragment of the present disclosure comprisesa constant region of human immunoglobulin lambda light chain.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure comprises one or more amino acid residuesubstitutions or modifications yet retains specific binding affinity toRBD of spike protein of SARS-CoV-2.

In some embodiments, the antibody or antigen binding fragment is anaffinity variant, a glycosylation variant, a cysteine-engineeredvariant, or an Fc variant.

In some embodiments, the glycosylation variant comprises a mutation atN297 (e.g. N297A, N297Q, or N297G), for example, to modify theglycosylation site.

In some embodiments, the Fc variant comprises one or more amino acidresidue modifications or substitutions resulting in increased effectorfunctions relative to a wildtype Fc. In some embodiments, the Fc variantcomprises one or more amino acid substitution(s) at one or more of thepositions selected from the group consisting of: 234, 235, 236, 238,239, 240, 241, 243, 244, 245, 246, 247, 248, 249, 252, 254, 255, 256,258, 260, 262, 263, 264, 265, 267, 268, 269, 270, 272, 274, 276, 278,280, 283, 285, 286, 289, 290, 292, 293, 294, 295, 296, 298, 299, 300,301, 303, 304, 305, 307, 309, 312, 313, 315, 320, 322, 324, 325, 326,327, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 340, 345, 360,373, 376, 378, 382, 388, 389, 396, 398, 414, 416, 419, 430, 433, 434,435, 436, 437, 438, 439 and 440 of the Fc region, wherein the numberingof the residues in the Fc region is that of the EU index as in Kabat. Insome embodiments, the Fc variant comprises one or more amino acidsubstitution selected from the group consisting of 234Y, 235Q, 236A,236W, 239D, 239E, 239M, 243L, 2471, 267E, 268D, 268E, 268F, 270E, 280H,290S, 292P, 298A, 298D, 298V, 300L, 3051, 324T, 326A, 326D, 326W, 330L,330M, 333S, 332D, 332E, 333A, 334A, 334E, 339D, 339Q, 345R, 396L, 430G,440Y, and any combination thereof. In some embodiments, the Fc varianthaving increased effector function comprises a combination of mutationsselected from the group consisting of: a) S239D, I332E, and A330L; b)F243L, R292P, Y300L, V305I and P396L; c) S239D and I332E; d) S239D,I332E and A330L; e) S298A, E333A and K334A; f) L234Y, L235Q, G236W,S239M, H268D, D270E and S298A (in one heavy chain) and D270E, K326D,A330M and K334E (in the opposing heavy chain); G236A, S239D and I332E;g) K326W and E333S; h) S267E, H268F and S324T; i) E345R, E430G andS440Y.

In some embodiments, the Fc variant comprises one or more amino acidresidue modifications or substitutions resulting in reduced effectorfunctions relative to a wildtype Fc. In some embodiments, the Fc variantcomprises one or more amino acid substitution(s) at a position selectedfrom the group consisting of: 220, 226, 229, 233, 234, 235, 236, 237,238, 267, 268, 269, 270, 297, 309, 318, 320, 322, 325, 328, 329, 330,and 331 of the Fc region, wherein the numbering of the residues in theFc region is that of the EU index as in Kabat. In some embodiments, theFc variant comprises one or more amino acid substitution(s) selectedfrom the group consisting of 220S, 226S, 228P, 229S, 233P, 234V, 234G,234A, 234F, 234A, 235A, 235G, 235E, 236E, 236R, 237A, 237K, 238S, 267R,268A, 268Q, 269R, 297A, 297Q, 297G, 309L, 318A, 322A, 325L, 328R, 330S,331S and any combination thereof. In some embodiments, the Fc varianthaving reduced effector function comprises a combination of mutationsselected from the group consisting of: a) K322A, L234A, and L235A; b)P331S, L234F, and L235E; c) L234A and L235A; c) N297A; d) N297Q; e)N297G; f) L235E; g) L234A and L235A (IgG1); h) F234A and L235A (IgG4);i) H268Q, V309L, A330S and P331S (IgG2); j) V234A, G237A, P238S, H268A,V309L, A330S and P331S (IgG2).

In some embodiments, the Fc variant comprises one or more amino acidresidue modifications or substitutions resulting in improved bindingaffinity to neonatal Fc receptor (FcRn) at pH 6.0 while retainingminimal binding at pH 7.4, or increased serum half life of the antibody.In some embodiments, the Fc variant comprises one or more amino acidsubstitution(s) at a position selected from the group consisting of: 234(e.g., with F), 235 (e.g., with Q), 238 (e.g., with D), 250 (e.g., withE or Q), 252 (e.g., with L/Y/F/W or T), 254 (e.g., with S or T), 256(e.g., with S/R/Q/E/D or T); 259 (e.g., with I); 272 (e.g., with A),305(e.g., with A), 307(e.g., with A or P), 308 (e.g., with F, C or P),311(e.g., with A or R), 312 (e.g., with A), 322 (e.g., Q), 328 (e.g. E),331 (e.g., with A), 378 (e.g., with A), 380 (e.g., with A), 382 (e.g.,with A), 428 (e.g., with L or F), 432 (e.g., with C), 433 (e.g., withH/L/R/S/P/Q or K), 434 (e.g., with H/F or Y or S or A or W), 435 (e.g.with H), 436 (e.g., with L) and 437 (e.g., with C)) (all positions by EUnumbering). In some embodiments, the Fc variant comprises one or moreamino acid substitution(s) selected from the group consisting of 234F,235Q, 238D, 250Q, 252T, 252Y, 254T, 256E, 2591, 272A, 305A, 307A, 308F,311A, 322Q, 328E, 331S, 380A, 428L, 432C, 433K, 433S, 434S, 434Y, 434F,434W, 434A, 435H, 436L, 437C and any combination thereof. In someembodiments, the Fc variant having increased serum half-life or improvedpH-dependent binding to FcRn comprises a combination of mutationsselected from the group consisting of: a) M428L and N434S; b) P238D andL328E; c) M252Y, S254T and T256E; d) L234F, L235Q, K322Q, M252T, S254Tand T256E; e) M428L, V259I and V308F; f) H433K and N434Y; g) H433K andN434F; h) T250Q and M428L; i) T307A, E380A and N434A; and j) 432C, 433S,434W, 435H, 436L, 437C.

In some embodiments, at least one of the substitutions or modificationsis in one or more of the CDR sequences. In some embodiments, at leastone of the substitutions or modifications is in one or more of thenon-CDR sequences of the heavy chain variable region or light chainvariable region. In some embodiments, at least one of the substitutionsis a conservative substitution.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure is a monoclonal antibody, a bispecific antibody, amulti-specific antibody, a recombinant antibody, a labeled antibody, abivalent antibody, an anti-idiotypic antibody, a fusion protein, or adimerized or polymerized antibody, or a modified antibody (e.g.glycosylated antibody). In some embodiments, the antibody or antigenbinding fragment of the present disclosure is a diabody, a Fab, a Fab′,a F(ab′)₂, a Fd, an Fv fragment, a disulfide stabilized Fv fragment(dsFv), a (dsFv)₂, a bispecific dsFv (dsFv-dsFv′), a disulfidestabilized diabody (ds diabody), a single-chain antibody molecule(scFv), an scFv dimer (bivalent diabody), a bispecific scFv dimer, amultispecific antibody, a heavy chain antibody, a camelized singledomain antibody, a nanobody, a domain antibody, or a bivalent domainantibody. In some embodiments, the antibody or antigen binding fragmentof the present disclosure is a full human antibody.

In some embodiments, the antibody or antigen binding fragment of thepresent disclosure is linked to one or more conjugate moieties. In someembodiments, the conjugate moiety comprises a therapeutic agent, aradioactive isotope, a detectable label, a pharmacokinetic modifyingmoiety, or a purifying moiety. In some embodiments, the conjugate moietyis covalently attached either directly or via a linker.

In one aspect, the present disclosure provides an isolated orrecombinant antibody or an antigen-binding fragment thereof, whichcompetes for binding to RBD of spike protein of SARS-CoV-2 with theantibody or an antigen-binding fragment thereof described herein.

In another aspect, the present disclosure provides bispecific antibodymolecules comprising an anti-SARS-CoV-2 antibody or antigen-bindingfragment thereof as disclosed herein.

In certain embodiments, the bispecific or bivalent antibodies providedherein comprises a first antigen-binding domain and a secondantigen-binding domain, wherein the first antigen-binding domains isderived from a monoclonal antibody selected from the group consisting ofP2A-1A8, P2A-1A9, P2B-2G11, P2A-1A10, P2A-1B3, P2B-2F6, P2B-2G4,P2C-1A3, P2C- 1C8, P2C-1C10, P2C-1D5, P2C-1F11, P2B-1G5, P2B-1A1,P2C-1D7, P2B-1A10, P2B-1D9, P2B-1E4, P2B-1G1, P4A-2D9, P5A-2G7, P5A-3C8,P5A-1D2, P5A-2F11, P5A-2E1, P5A-1C8, P1A-1C10, P4A-1H6, P4B-1F4,P5A-1B6, P5A-1B8, P5A-1B9, P5A-1D1, P5A-1D10, P5A-2D11, P5A-2G9,P5A-2H3, P5A-3A1, P5A-3A6, P5A-3B4, P5A-3C12, and P22A-1D1. The secondantigen-binding domain can be derived from any suitable antibody.

In certain embodiments, the bispecific antibodies provided hereincomprises a first antigen-binding domain and a second antigen-bindingdomain, wherein the first and the second antigen-binding domains arederived from any two monoclonal antibodies selected from the groupconsisting of P2A-1A8, P2A-1A9, P2B-2G11, P2A-1A10, P2A-1B3, P2B-2F6,P2B-2G4, P2C-1A3, P2C-1C8, P2C-1C10, P2C-1D5, P2C-1F11, P2B-1G5,P2B-1A1, P2C-1D7, P2B-1A10, P2B-1D9, P2B-1E4, P2B-1G1, P4A-2D9, P5A-2G7,P5A-3C8, P5A-1D2, P5A-2F11, P5A-2E1, P5A-1C8, P1A-1C10, P4A-1H6,P4B-1F4, P5A-1B6, P5A-1B8, P5A-1B9, P5A-1D1, P5A-1D10, P5A-2D11,P5A-2G9, P5A-2H3, P5A-3A1, P5A-3A6, P5A-3B4, P5A- 3C12, and P22A-1D1. Incertain embodiments, the first and the second antigen-binding domainsare derived from P2C-1F11 and P2B-2F6, respectively. In certainembodiments, the first and the second antigen-binding domains arederived from P2C-1F11 and P2B-1G5, respectively.

In certain embodiments, the bispecific antibody molecules have at leasttwo distinct antigen-binding sites with different specificities.

In certain embodiments, the bispecific antibody molecules providedherein are capable of binding to different epitopes on the spike proteinof SARS-CoV-2 virus. In some embodiments, the two or more antibodiesbind to different epitopes in RBD of spike protein of SARS-CoV-2.

In certain embodiments, the bispecific antibody molecules providedherein has a first antigen-binding domains specificity directed to theRBD of the spike protein of SARS-CoV-2 virus and a secondantigen-binding domains specificity directed to a second antigen.

In another aspect, the present disclosure provides an isolatedpolynucleotide encoding the antibody or antigen binding fragment thereofas described herein.

In some embodiments, the isolated polynucleotide of the presentdisclosure comprises a nucleotide sequence selected from a groupconsisting of: SEQ ID NOs: 9-10, 19-20, 29-30, 39-40, 49-50, 59-60,63-64, 73-74, 83-84, 93-94, 103-104, 113-114, 144-145, 154-155, 164-165,174-175, 184-185, 194-195, 204-205, 214-215, 224-225, 234-235, 244-245,254-255, 264-265, 274-275, 284-285, 294-295, 304-305, 314-315, 324-325,334-335, 344-345, 354-355, 364-365, 374-375, 384-385, 394-395, 404-405,414-415, 424-425, and 434-435, or a homologous sequence thereof havingat least 80% sequence identity.

In some embodiments, the homologue sequence encodes the same protein asencoded by any nucleotide sequence selected from the group consisting ofSEQ ID NOs: 9-10, 19-20, 29-30, 39-40, 49-50, 59-60, 63-64, 73-74,83-84, 93-94, 103-104, 113-114, 144-145, 154-155, 164-165, 174-175,184-185, 194-195, 204-205, 214-215, 224-225, 234-235, 244-245, 254-255,264-265, 274-275, 284-285, 294-295, 304-305, 314-315, 324-325, 334-335,344-345, 354-355, 364-365, 374-375, 384-385, 394-395, 404-405, 414-415,424-425, and 434-435.

In one aspect, the present disclosure provides a vector comprising theisolated polynucleotide of the present disclosure. In some embodiments,said vector is an expression vector.

In one aspect, the present disclosure provides a host cell comprisingthe vector of the present disclosure.

In one aspect, the present disclosure provides a method of producing theantibody or antigen binding fragment of the present disclosure. In someembodiments, the method comprises culturing the host cell of the presentdisclosure under the condition at which the expression vector of thepresent disclosure is expressed. In some embodiments, the method of thepresent disclosure further comprises purifying the antibody produced bythe host cell.

In some embodiments, the pharmaceutical composition disclosed herein cancomprise a combination of two or more antibodies or antigen bindingfragments of the present disclosure. In some embodiments, thepharmaceutical composition comprises a combination of two or moremonoclonal antibodies, each of which comprises heavy chain CDR sequencesand light chain CDR sequences derived from an antibody selected from thegroup consisting of P2A-1A8, P2A-1A9, P2B-2G11, P2A-1A10, P2A-1B3,P2B-2F6, P2B-2G4, P2C-1A3, P2C-1C8, P2C-1C10, P2C-1D5, P2C-1F11,P2B-1G5, P2B-1A1, P2C-1D7, P2B-1A10, P2B-1D9, P2B- 1E4, P2B-1G1,P4A-2D9, P5A-2G7, P5A-3C8, P5A-1D2, P5A-2F11, P5A-2E1, P5A-1C8,P1A-1C10, P4A-1H6, P4B-1F4, P5A-1B6, P5A-1B8, P5A-1B9, P5A-1D1,P5A-1D10, P5A- 2D11, P5A-2G9, P5A-2H3, P5A-3A1, P5A-3A6, P5A-3B4,P5A-3C12, and P22A-1D1.

In certain embodiments, the pharmaceutical composition comprises a firstantibody comprising heavy chain CDR sequences and light chain CDRsequences derived from P2C-1F11, and a second antibody comprising heavychain CDR sequences and light chain CDR sequences derived from antibodyP2B-2F6. In certain embodiments, the pharmaceutical compositioncomprises a first antibody comprising heavy chain CDR sequences andlight chain CDR sequences derived from P2C-1F11, and a second antibodycomprising heavy chain CDR sequences and light chain CDR sequencesderived from antibody P2B-1G5.

In some embodiments, the two or more antibodies or antigen bindingfragments bind to different epitopes in RBD of spike protein ofSARS-CoV-2. In some embodiments, the two or more antibodies comprise afirst antibody which comprises P2C-1F11 or an antigen binding fragmentthereof, and a second antibody which is selected from the groupconsisting of P2C-1A3, P2C-1C10, P2B-2F6, P2B-1G5, and P2A-1B3, or anantigen binding fragment thereof. In some embodiments, the two or moreantibodies comprise a first antibody which comprises P2C-1A3 or anantigen binding fragment thereof, and a second antibody which isselected from the group consisting of P5A-3C8, P5A-1D2, P22A-1D1,P2C-1F11, and P2A-1B3, or an antigen binding fragment thereof. In someembodiments, the two or more antibodies comprise a first antibody whichcomprises P2B-2F6 or an antigen binding fragment thereof, and a secondantibody selected from the group consisting of P5A-3C8, P5A-1D2,P22A-1D1, P2C-1C10, P2C-1F11, P2B-1G5, and P2A-1B3, or an antigenbinding fragment thereof. In some embodiments, the two or moreantibodies comprise a first antibody which comprises P2A-1B3 or anantigen binding fragment thereof, and a second antibody selected fromthe group consisting of P5A-3C8, P5A-1D2, P22A-1D1, P2C-1A3, P2C-1C10,P2C-1F11, P2B-2F6, and P2A-1A10, or an antigen binding fragment thereof.In some embodiments, the two or more antibodies comprise a firstantibody which comprises P2C-1C10 or an antigen binding fragmentthereof, and a second antibody selected from the group consisting ofP5A-3C8, P5A-1D2, P22A-1D1, P2C-1A3, P2C-1F11, and P2A-1B3, or anantigen binding fragment thereof

In some embodiments, the pharmaceutical compositions comprise thepolynucleotides encoding the anti-SARS-CoV-2 antibodies or theantigen-binding fragments thereof, and one or more pharmaceuticallyacceptable carriers. The present disclosure further providespharmaceutical compositions comprising the polynucleotides encoding thecombination of the two or more anti-SARS-CoV-2 antibodies or theantigen-binding fragments thereof, and one or more pharmaceuticallyacceptable carriers. In certain embodiments, the polynucleotidescomprise an expression vector. In certain embodiments, the expressionvector comprises a viral vector or a non-viral vector. In certainembodiments, the expression vector is suitable for gene therapy inhuman. In certain embodiments, the expression vector comprises a DNAvector or a RNA vector.

In some embodiments, the pharmaceutical composition further comprises asecond bioactive agent, such as a second therapeutic agent or a secondprophylactic agent.

In one aspect, the present disclosure provides a kit for detecting aSARS-CoV-2 antigen, comprising the antibody or antigen binding fragmentof the present disclosure. In some embodiments, the kit of furthercomprises a control reagent comprising RBD of spike protein of theSARS-CoV-2. In some embodiments, the kit further comprises a set ofreagents for detecting complex of the antibody or the antigen-bindingfragment bound to the SARS-CoV-2 antigen.

In one aspect, the present disclosure provides a method of treatingSARS-CoV-2 infection in a subject. The present disclosure also providesmethods of treating a disease, disorder or condition associated withSARs-CoV-2 infection in a subject. In some embodiments, the methodcomprises administering a therapeutically effective amount of one ormore of the antibody, the antigen binding fragment, or one or morepolynucleotides encoding one or more of the antibody or antigen-bindingfragment thereof provided herein, or the pharmaceutical composition ofthe present disclosure to the subject.

In one aspect, the present disclosure provides a method of preventingSARS-CoV-2 infection in a subject. The present disclosure also providesmethods of preventing a disease, disorder or condition associated withSARs-CoV-2 infection in a subject. In some embodiments, the methodcomprises administering a prophylactically effective amount of one ormore of the antibody or antigen binding fragment, or the pharmaceuticalcomposition of the present disclosure to the subject.

In some embodiments, the administration is via oral, nasal, intravenous,subcutaneous, or intramuscular administration. In some embodiments, thesubject is human. In some embodiments, the polynucleotide providedherein can be administered to a subject by, for example, transfectiontechniques such as electroporation, or hydrodynamic injection. In someembodiments, the polynucleotides comprise viral vectors such as AAV, andcan be administered via local injection (e.g. intramuscular, intranasal,intradermal, subcutaneous, etc.) or systematic administration (e.g.intravenous administration).

In some embodiments, the method further comprises administering atherapeutically effective amount of a second bioactive agent which canbe a therapeutic agent or a prophylactic agent. In some embodiments, thesecond therapeutic agent is an anti-viral agent. In some embodiments, ananti-viral agent comprises an antiviral peptide, an anti-viral antibody,an anti-viral compound, an anti-viral cytokine, or an anti-viraloligonucleotide. In some embodiments, the second therapeutic agent is anRNA dependent RNA polymerase inhibitor, a non-nucleoside reversetranscriptase inhibitor (NNRTI), nucleoside reverse transcriptaseinhibitor (NRTI), purine nucleoside, antiviral interferon, adamantineantiviral compound, or any other suitable antiviral agent. In someembodiments, the second therapeutic agent is remdesivir, chloroquine,hydroxychloroquine, lopinavir, ritonavir, APN01, favilavir, mesalazine,toremifene, eplerenone, paroxetine, sirolimus, dactinomycin, irbesartan,emodin, mercaptopurine, melatonin, quinacrine, carvedilol, colchicine,camphor, equilin, oxymetholone, nafamosta, camostat, baricitinib,darunavir, ribavirin, galidesivir, BCX-4430, Arbidol, nitazoxanide,derivatives thereof, or any combination thereof.

In one aspect, the present disclosure provides a method of detectingpresence or amount of SARS-CoV-2 virus antigen in a sample. In someembodiments, the method comprises contacting the sample with one or moreof the antibody or antigen binding fragment of the present disclosure,and determining the presence or the amount of the SARS-CoV-2 virusantigen in the sample.

In one aspect, the present disclosure provides use of one or more of theantibody or antigen binding fragment of the present disclosure in themanufacture of a medicament for treating or preventing SARS-CoV-2infection or a disease, disorder or condition associated with SARs-CoV-2infection. In one aspect, the present disclosure provides use of one ormore of the antibody or antigen binding fragment of the presentdisclosure in the manufacture of a medicament for preventing, managing,treating and/or ameliorating in a subject a disease or a disorder causedby or associated with coronavirus (e.g. SARs-COV-2) infection and/or asymptom or respiratory condition relating thereto.

In one aspect, the present disclosure provides use of one or more of theantibody or antigen binding fragment of the present disclosure in themanufacture of a diagnostic reagent for detecting SARS-CoV-2 infection.

In one aspect, the present disclosure provides a kit for detecting anantibody capable of specifically binding to receptor-binding domain(RBD) of the spike protein of SARS-CoV-2, comprising a polypeptidecomprising an amino acid sequence comprising SEQ ID NO: 128. In someembodiments, the polypeptide is immobilized on a substrate. In someembodiments, the kit further comprises a set of reagents for detectingcomplex of the antibody bound to the polypeptide.

In one aspect, the present disclosure provides a method of detectingpresence or amount of an antibody capable of specifically binding to RBDof the spike protein of SARS-CoV-2 in a sample, comprising contactingthe sample with a polypeptide comprising an amino acid sequencecomprising SEQ ID NO: 128, and determining the presence or the level ofthe antibody in the sample. In some embodiments, the absence of theantibody in the sample or the level of the antibody in the sample beingbelow a threshold indicates that the subject is more likely to sufferfrom disease progression.

In another aspect, the present disclosure provides a method ofdetermining the likelihood of disease progression in a subject infectedwith SARS-CoV-2, the method comprising: contacting a sample obtainedfrom the subject with a polypeptide comprising an amino acid sequencecomprising SEQ ID NO: 128, and detecting the presence or the level of anantibody in the sample wherein the antibody is capable of specificallybinding to RBD of the spike protein of the SARS-CoV-2, wherein thesubject is likely to experience disease progression when the antibody inthe sample is absent or is below a threshold.

In yet another aspect, the present disclosure provides a method ofmonitoring treatment response in a subject infected with SARS-CoV-2 andreceived a treatment, the method comprising: (i) contacting a samplefrom the subject with a peptide comprising an amino acid sequence of SEQID NO: 128; (ii) detecting a first level of an antibody in the samplewherein the antibody is capable of specifically binding to RBD of thespike protein of the SARS-CoV-2; and (iii) comparing the first level ofthe antibody with a second level of the antibody detected in the subjectprior to the treatment; wherein the first level being higher than thesecond level indicates that the subject is responsive to the treatment.

In yet another aspect, the present disclosure provides a method ofneutralizing SARS-CoV-2 in a subject or in a sample in vitro, comprisingadministering a therapeutically effective amount of one or more of theantibody or antigen binding fragment thereof provided herein, or thepharmaceutical composition provided herein to the subject or to thesample.

In yet another aspect, the present disclosure provides a crystal of RBDof the spike protein of SARS-CoV-2 in complex with an antibody. In someembodiments, the antibody in complex with the RBD comprises a heavychain variable region of SEQ ID NO: 47 and a light chain variable regionof SEQ ID NO: 48. In some embodiments, the antibody in complex with theRBD comprises a heavy chain variable region of SEQ ID NO: 111 and alight chain variable region of SEQ ID NO: 112.

In some embodiment, the crystal has or consists of a P2₁2₁2₁ space groupwith unit cell dimensions of a=70.23 Å, b=90.15 Å, and c=112.35 Å.

In some embodiment, the crystal has or consists of a C121 space groupwith unit cell dimensions of a=194.88 Å, b=85.39 Å, and c=58.51 Å.

In some embodiment, the crystal has or consists of a C2 space group withunit cell dimensions of a=193.34 Å, b=86.60 Å, and c=57.16 Å.

In some embodiment, the crystal has or consists of a C2 space group withunit cell dimensions of a=158.75 Å, b=67.51 Å, and c=154.37 Å.

In some embodiment, the crystal has or consists of a P2₁2₁2₁ space groupwith unit cell dimensions of a=112.54 Å, b=171.57 Å, and c=54.87 Å.

BRIEF DESCRIPTION OF FIGURES

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentdisclosure. The disclosure may be better understood by reference to oneor more of these drawings in combination with the detailed descriptionof specific embodiments presented herein.

FIG. 1A-FIG. 1F. Analyses of plasma and B cell responses specific toSARS-CoV-2. Serial dilutions of plasma samples were analyzed for bindingto the (FIG. 1A) RBDs or (FIG. 1B) trimeric Spikes of SARS-CoV-2,SARS-CoV and MERS-CoV by ELISA and (FIG. 1C) for neutralizing activityagainst pseudoviruses bearing envelope glycoprotein of SARS-CoV-2,SARS-CoV and MERS-CoV. Binding to SARS-CoV-2 NP protein was alsoevaluated (A). All results were derived from at least two independentexperiments. (FIG. 1D) Gating strategy for analysis and isolation ofRBD-specific memory B cells and (FIG. 1E and FIG. 1F) theirrepresentation among the total and memory subpopulation of B cells inthe eight study subjects. Samples were named as either A, B, or Cdepending on collection sequence. FSC-W, forward scatter width; FSC-A,forward scatter area; and SSC-A side scatter area.

FIG. 2. Heavy chain repertoires of SARS-CoV-2 RBD-specific antibodiesanalyzed by individual subject. Distribution and frequency of heavychain variable (VH) genes usage in each subject shown along thehorizontal bar. The same color scheme is used for each VH family acrossall study subjects. The VHs that dominate across isolated antibodies areindicated by actual frequencies in their respective color boxes. Thenumber of RBD-binding antibodies versus total antibodies isolated areshown on the right.

FIG. 3A-FIG. 3F. Clonal expansion of specific heavy and light chainfamilies in the P#2 antibody repertoire. (FIG. 3A) Phylogenetic analysisof VH (left) and VL 20 (right) genes for all RBD-binding antibodies.Clonal expanded VH and VL clusters are paired and highlighted in threedifferent colors. Branch lengths are drawn to scale so that sequencerelatedness can be readily assessed. (FIG. 3B)-(FIG. 3C) Clonalexpansion in relation to members of other VH and VL families based onsomatic hypermutations (SHM) and CDR3 loop lengths. For the pie chartsof VH (left) and VL (right) genes, the radii represent the CDR3 looplength and the color scale indicates the degree of SHM. Heavy and lightchain repertoires for each antibody are shown along the pie circles.(FIG. 3D)-(FIG. 3E) Lineage analysis for heavy and light chains in piecharts. The numbers in the center represent the number of RBD-specificantibodies. Each slice represents a unique clone and proportional to itsown size. (FIG. 3F) Counts of various HCDR3 length from IGHV3-53 andIGHV3-66 as well as RBD binders.

FIG. 4A-FIG. 4V. Antibody binding, competition with ACE2, andneutralization analyzed by pseudovirus and live SARS-CoV-2. (FIG. 4A)Binding kinetics of representative mAbs to SARS-CoV-2 RBD measured bySPR. The black lines indicate the experimentally derived curves whilethe grey lines represent fitted curves based on the experimental data.(FIG. 4B) Antibody and ACE2 competition for binding to SARS-CoV-2 RBDmeasured by SPR. The sensorgrams show distinct binding patterns of ACE2to SARS-CoV-2 RBD with or without prior incubation with eachrepresentative antibody. (FIG. 4C and FIG. 4D) Antibody neutralizationanalyzed by SARS-CoV-2 RBD binding assay. (FIG. 4E through FIG. 4R)Antibody neutralization analyzed by pseudovirus assay. (FIG. 4S)-(FIG.4T) Antibody neutralization analyzed by live SARS-CoV-2 neutralizationassay, in which dashed lines indicated 50% reduction in viralinfectivity. VRC01 is an HIV-1 specific antibody and used here as anegative control. (FIG. 4U)-(FIG. 4V) Summary of actual values fromstudies in FIG. 4A through FIG. 4T. Antibody binding to RBD waspresented either by Kd or by competing with ACE2 where “+++”indicates >80% competition; “++” indicates 50-80%; “+” indicates 20-50%;and “−” indicates<20%. IC₅₀ represents the half-maximal whereas IC₈₀ the80% inhibitory concentrations and IC₉₀ the 90% inhibitory concentrationstested in the pseudovirus and live SARS-CoV-2 neutralization assay. Onlythe antibody heavy chains are indicated at the upper left corner fortheir family designation, CDR3 length, and SHM in relative tocorresponding germline ancestor sequence. n.d. not done.

FIG. 5A-FIG. 5T. Crystal structures of 2F6 and P2C-1F11 in complex withSARS-CoV-2 RBD respectively, and the lists of determined contactingresidues at the antibody/SARS-CoV-2 interfaces. (FIG. 5A) Overallstructure of 2F6 Fab in complex with SARS-CoV-2 RBD. (FIG. 5B) Thecritical interactions between 2F6 and SARS-CoV-2 RBD. (FIG. 5C) 2F6/RBDcomplex was aligned to ACE2/RBD complex (PDB ID: 6M0J). Circle indicatedthe clash between ACE2 and 2F6. (FIG. 5D) The SARS-CoV-2 spike (PDB ID:6VSB) is shown as a molecular surface, with each protomer colored eitherlight orange, blue and green. 2F6/RBD complex could be aligned to boththe “up” RBD (light orange) and the “down” RBD (light blue) in spike.2F6 heavy chain is colored in magenta, 2F6 light chain in yellow,SARS-CoV-2 RBD in cyan, and ACE2 in green. (FIG. 5E) Contacting residuesat the SARS-CoV-2/2F6 interface. (FIG. 5F) Overall structure of P2C-1F11Fab in complex with SARS-CoV-2 RBD. (FIG. 5G) Contacting residues at theSARS-CoV-2/1F11 interface. (FIG. 5H)-(FIG. 5K) Overall structures,crystal structures of the RBD and Fab complexes and RBD binding residuesshared with ACE2 were shown for antibodies P22A-1D1, P5A-1D2, P5A-3C8and P2C-1F11 respectively. (FIG. 5I) The footprint of Fabs and ACE2 onSARS-CoV-2 RBD. The color of the epitope was depicted as in panel (FIG.5H). The epitope of ACE2 was colored by green. (J) (FIG. 5M) ConservedHCDR1, HCDR2 and different HCDR3. RBD was shown as surface. CDR loops ofthe heavy chain were shown as ribbons. (FIG. 5N) The interactionsbetween the three conserved tyrosine at HCDR1 and HCDR2. (FIG. 5O) Theinteractions between HCDR2 -SGGS- segment and RBD. Hydrogen bonds wereshown as black dashed line and P5A-3C8/RBD complex was used as anexample in panel L and M. Y505 residue on RBD protruded into the wedgehole of the light chain For P22A-1D1 (FIG. 5Q), P5A-3C8 (FIG. 5R) andP2C-1F11 (FIG. 5S), whereas for P5A-1D2 (FIG. 5P) Y505 displayed adifferent conformation because of the binding of the long HCDR3. (FIG.5T) Summary of contacts between SARS-CoV-2 RBD and P22A-1D1, P5A-3C8,P5A-1D2, P2C-1F11 (distance cutoff 4 Å).

FIG. 6A-FIG. 6C. Analysis of plasma binding to cell surface expressedtrimeric Spike protein. (FIG. 6A) and (FIG. 6B) HEK 293T cellstransfected with expression plasmid encoding the full length spike ofSARS-CoV-2, SARS-CoV or MERS-CoV were incubated with 1:100 dilutions ofconvalescent plasma from the study subjects. The cells were then stainedwith PE labeled anti-human IgG Fc secondary antibody and analyzed byFACS. Positive control antibodies include S230 and m396 targeting theRBD of SARS-CoV Spike, and Mab-GD33 targeting the RBD of MERS-CoV Spike.VRC01 is negative control antibody targeting HIV-1 envelopeglycoprotein. (FIG. 6C) Impact of epitope mutations on binding ofantibodies P22A-1D1, P5A-1D2, P5A-3C8, P2C-1F11 and P2B-2F6. Cellsurface expressed wild type or mutant spike glycoprotein of SARS-Cov-2were incubated with the ACE2, the tested antibodies, and controlantibodies S2 mAb, followed by staining with anti-human IgG Fc PE (foridentified human antibodies), anti-mouse IgG FITC (for S2 mAb) oranti-his PE (for ACE2) secondary antibody and analyzed by FACS. P2B-2F6recognizes a distinct epitope on SARS-CoV-2 RBD from those publicantibodies and used here as positive control for the S1 protein of thespike. S2 is a mouse monoclonal specific for S2 protein of the spike.The cell percentage in the gate are shown. Mutants that resulted in morethan 80% reduction in binding are highlighted in either grey boxes forpublic antibodies or in orange boxes for ACE2. The percent reduction wasdetermined by the MFI weighted by multiplying the number of positivecells in the selected gates and normalized in relative to that of wildtype and S2 control. Data shown were from at least two independentexperiments.

FIG. 7A-FIG. 7K. RBD-specific memory B cells analyzed and isolatedthrough FACS (FIG. 7A)-(FIG. 7K). The recombinant RBD was labeled witheither a Strep or His tag and used alone or in combination to identifyand isolate RBD-specific single B cells through staining with theStreptavidin-APC and/or Streptavidin-PE, or anti-His-APC and anti-His-PEantibodies. B cells to be isolated are highlighted in boxes or ovals.Samples were named as either A, B, or C depending on collectionsequence. FSC-W, forward scatter width; FSC-A, forward scatter area; andSSC-A side scatter area.

FIG. 8. ELISA screening of SARS-CoV-2 RBD-specific antibodies in thesupernatant of transfected cells. The study subjects and the date ofsampling are indicated on the top. Samples were named as either A, B, orC depending on collection sequence. Antibodies tested for each sampleare aligned in one vertical column whenever possible. For each evaluatedantibody, at least two independent measurements were performed and arepresented adjacently on the same row. Binding activities were assessedby OD 450 and indicated by the color scheme on the right. Negatives (nobinding activity) are shown in gray for OD 450 values less than 0.1.

FIG. 9A-FIG. 9G. Binding kinetics of isolated mAbs with SARS-CoV-2 RBDmeasured by SPR and ELISA respectively. (FIG. 9A, FIG. 9B) For SPR, thepurified soluble SARS-CoV-2 RBD, SARS-CoV RBD and MERS-CoV2 RBD werecovalently immobilized onto a CM5 sensor chip followed by injection ofindividual antibody at five different concentrations. The black linesindicate the experimentally derived curves while the grey linesrepresent fitted curves based on the SPR experimental data. For ELISAanalysis, recombinant SARS-CoV RBD and MERS-CoV2 RBD were coated on theELISA plate, and a serial dilution of each antibody was evaluatedagainst SARS-CoV RBD and MERS-CoV2 RBD coated plates respectively andtheir binding activity was recorded at an optical density (OD) of 450 nmand 630 nm. (FIG. 9C-FIG. 9F) For ELISA analysis, S230 was used as apositive control antibody against SARS-COV, MAB-GD33 was used as apositive control antibody against MERS-COV, and VRC01 was used asnegative control antibody. (FIG. 9G) Binding kinetics of isolated mAbswith SARS-CoV-2 RBD were measured by SPR.

FIG. 10A-FIG. 10C. Antibody and ACE2 competition for binding toSARS-CoV-2 RBD measured by SPR for patient #2 (FIG. 10A), patient #1(FIG. 10B), and patient#5, #22 and #2 (FIG. 10C). The sensorgrams showdistinct binding patterns of ACE2 to SARS-CoV-2 RBD with (correspondingto curves for “antibody+ACE2”) or without (corresponding to curves for“ACE2”) prior incubation with each testing antibody. The competitioncapacity of each antibody is indicated by the level of reduction inresponse unit of ACE2 comparing with or without prior antibodyincubation.

FIG. 11A-FIG. 11B. Analysis of antibody binding to cell surfaceexpressed trimeric Spike protein. HEK 293T cells transfected withexpression plasmid encoding the full length spike of SARS-CoV-2,SARS-CoV or MERS-CoV were incubated with 20 ug/ml testing antibodies(FIG. 11A) and (FIG. 11B). The cells were then stained with PE labeledanti-human IgG Fc secondary antibody and analyzed by FACS. Positivecontrol antibodies include S230 and m396 targeting the RBD of SARS-CoVSpike, and Mab-GD33 targeting the RBD of MERS-CoV Spike. VRC01 is thenegative control antibody targeting HIV-1 envelope glycoprotein.

FIG. 12A-FIG. 12D. Neutralization activity of mAbs against liveSARS-CoV-2 analyzed by focus reduction neutralization test (FRNT).Serial dilution of each antibody was tested against live SARS-CoV-2infection. Their neutralizing activities are represented by thereduction in the number of SARS-CoV-2 foci calculated by an EliSpotreader (Cellular Technology Ltd) (FIG. 12A)-(FIG. 12D).

FIG. 13. Epitope mapping through competitive binding measured by SPR.The sensorgrams show distinct binding patterns when pairs of testingantibodies were sequentially applied to the purified SARS-CoV-2 RBDcovalently immobilized onto a CM5 sensor chip. The level of reduction inresponse unit comparing with or without prior antibody incubation is thekey criteria for determining the two mAbs recognize the separate orclosely situated epitopes.

FIG. 14. Multiple sequence alignment of the CDR1-CDR3 regions of theheavy chain sequences from the public clonetypes. Included areantibodies P22A-1D1 (SEQ ID NO: 432), P5A-1D2 (SEQ ID NO: 242), P5A-3C8(SEQ ID NO: 232) and P2C-1F11(SEQ ID NO: 111) along with IGVH3-53 (SEQID NO: 436) and/IGVH3-66(SEQ ID NO: 437), a top germline alleleassignment for public antibodies shown. Grey letters show mutations fromgermline.

FIG. 15A-FIG. 15B. Antibody individual PK profiles of singleadministration fit the population PK prediction model and themeasurement data for mAb1 (FIG. 15A) and mAb2 (FIG. 15B). Solid lines:predicted medians. Dashed lines and the dots: measured concentrations inthe subjects. The shaded areas represent the 5th-95th percentiles.

FIG. 16. In vitro Neutralization Activity of mAb1 and mAb2 Combinationin SARS-CoV-2 Live Virus Micro-Neutralization Assay.

FIG. 17A-FIG. 17B. Mean serum concentration profiles of in cynomolgusmonkeys following single IV infusion administration of at 10 mg/kg formAb1 (FIG. 17A) and mAb2 (FIG. 17B).

DETAILED DESCRIPTION

Throughout the present disclosure, the articles “a”, “an” and “the” areused herein to refer to one or to more than one (i.e., to at least one)of the grammatical object of the article. By way of example, “anantibody” means one antibody or more than one antibody.

The features and advantages of the disclosed compositions and methodswill be more readily understood, by those of ordinary skill in the art,from reading the following detailed description. It is to be appreciatedthat certain features of the disclosed compositions and methods, whichare, for clarity, described above and below in the context of separateembodiments, may also be provided in combination in a single embodiment.Conversely, various features of the disclosed compositions and methodsthat are, for brevity, described in the context of a single embodiment,may also be provided separately or in any sub-combination. In addition,references in the singular may also include the plural (for example, “a”and “an” may refer to one, or one or more) unless the contextspecifically states otherwise.

The use of numerical values in the various ranges specified in thisapplication, unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within thestated ranges were both proceeded by the word “about.” In this manner,slight variations above and below the stated ranges can be used toachieve substantially the same results as values within the ranges.Also, the disclosure of these ranges is intended as a continuous rangeincluding every value between the minimum and maximum values.

The term “about” and its grammatical equivalents in relation to areference numerical value and its grammatical equivalents as used hereincan include a range of values plus or minus 10% from that value, such asa range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or1% from that value. For example, the amount “about 10” includes amountsfrom 9 to 11.

Definitions

Antibody Related Terms

The term “antibody” as used herein includes any immunoglobulin,monoclonal antibody, polyclonal antibody, monovalent antibody, bivalentantibody, multivalent antibody, bispecific antibody, multi-specificantibody that binds to a specific antigen. A native intact antibodycomprises two heavy (H) chains and two light (L) chains. Mammalian heavychains are classified as alpha, delta, epsilon, gamma, and mu, eachheavy chain consists of a variable region (VH) and a first, second,third, and optionally fourth constant region (CH1, CH2, CH3, CH4respectively); mammalian light chains are classified as λ or κ, whileeach light chain consists of a variable region (VL) and a constantregion. The antibody has a “Y” shape, with the stem of the Y consistingof the second and third constant regions of two heavy chains boundtogether via disulfide bonding. Each arm of the Y includes the variableregion and first constant region of a single heavy chain bound to thevariable and constant regions of a single light chain. The variableregions of the light and heavy chains are responsible for antigenbinding. The variable regions in both chains generally contain threehighly variable loops called the complementarity determining regions(CDRs) (light chain CDRs including LCDR1, LCDR2, and LCDR3, heavy chainCDRs including HCDR1, HCDR2, HCDR3). CDR boundaries for the antibodiesand antigen-binding fragments disclosed herein may be defined oridentified by the conventions of Kabat, IMGT, Chothia, or Al-Lazikani(Al-Lazikani, B., Chothia, C., Lesk, A. M., J Mol. Biol., 273(4), 927(1997); Chothia, C. et al., J Mol Biol. December 5; 186(3):651-63(1985); Chothia, C. and Lesk, A. M., J Mol. Biol., 196,901 (1987);Chothia, C. et al., Nature. December 21-28; 342(6252):877-83 (1989);Kabat E. A. et al., Sequences of Proteins of immunological Interest, 5thEd. Public Health Service, National Institutes of Health, Bethesda, Md.(1991); Marie-Paule Lefranc et al., Developmental and ComparativeImmunology, 27: 55-77 (2003); Marie-Paule Lefranc et al., ImmunomeResearch, 1(3), (2005); Marie-Paule Lefranc, Molecular Biology of Bcells (second edition), chapter 26, 481-514, (2015)). The three CDRs areinterposed between flanking stretches known as framework regions (FRs)(light chain FRs including LFR1, LFR2, LFR3, and LFR4, heavy chain FRsincluding HFR1, HFR2, HFR3, and HFR4), which are more highly conservedthan the CDRs and form a scaffold to support the highly variable loops.The constant regions of the heavy and light chains are not involved inantigen-binding, but exhibit various effector functions. Antibodies areassigned to classes based on the amino acid sequences of the constantregions of their heavy chains. The five major classes or isotypes ofantibodies are IgA, IgD, IgE, IgG, and IgM, which are characterized bythe presence of alpha, delta, epsilon, gamma, and mu heavy chains,respectively. Several of the major antibody classes are divided intosubclasses such as IgG1 (gammal heavy chain), IgG2 (gamma2 heavy chain),IgG3 (gamma3 heavy chain), IgG4 (gamma4 heavy chain), IgA1 (alpha1 heavychain), or IgA2 (alpha2 heavy chain).

The term “antigen-binding fragment” as used herein refers to an antibodyfragment formed from a portion of an antibody comprising one or moreCDRs, or any other antibody fragment that binds to an antigen but doesnot comprise an intact native antibody structure. Examples ofantigen-binding fragment include, without limitation, a diabody, a Fab,a Fab′, a F(ab′)₂, a Fd, an Fv fragment, a disulfide stabilized Fvfragment (dsFv), a (dsFv)₂, a bispecific dsFv (dsFv-dsFv′), a disulfidestabilized diabody (ds diabody), a single-chain antibody molecule(scFv), an scFv dimer (bivalent diabody), a bispecific scFv dimer, asingle-chain Fv-Fc antibody (scFv-Fc), a camelized single domainantibody, a nanobody, a domain antibody, and a bivalent domain antibody.An antigen-binding fragment is capable of binding to the same antigen towhich the parent antibody binds.

As used herein, a “bispecific” antibody refers to an artificial antibodywhich has fragments derived from two different monoclonal antibodies. Abispecific antibody may bind to overlapping epitopes or to two differentepitopes. The two epitopes may present on the same antigen, or they maypresent on two different antigens. As such, the terms “multi-specific”antibody refers to an artificial antibody which has fragments derivedfrom multiple different monoclonal antibodies, and may be capable ofbinding to more than one epitope.

The term “chimeric” as used herein, means an antibody or antigen-bindingfragment, having a portion of heavy and/or light chain derived from onespecies, and the rest of the heavy and/or light chain derived from adifferent species.

The term “epitope” as used herein refers to the specific group of atomsor amino acids on an antigen to which an antibody binds. Two antibodiesmay bind the same or a closely related epitope within an antigen if theyexhibit competitive binding for the antigen. An epitope can be linear orconformational (i.e. including amino acid residues spaced apart). Forexample, if an antibody or antigen-binding fragment blocks binding of areference antibody to the antigen by at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, or at least 90%, or at least 95%, then the antibody orantigen-binding fragment may be considered to bind the same/closelyrelated epitope as the reference antibody. The capacity to block, orcompete with, the binding of the antibody or the antigen-bindingfragment of the present disclosure to SARS-CoV-2 typically indicatesthat an antibody or the antigen-binding fragment to be screened binds toan epitope or binding site on SARS-CoV-2 that structurally overlaps withthe binding site on SARS-CoV-2 that is immunospecifically recognized bythe antibody or the antigen-binding fragment of the present disclosure.Alternatively, this can indicate that an antibody or an antigen-bindingfragment of the present disclosure to be screened binds to an epitope orbinding site that is sufficiently proximal to the binding siteimmunospecifically recognized by the antibody or the antigen-bindingfragment of the present disclosure to sterically or otherwise inhibitbinding of the antibodies or the antigen-binding fragment of the presentdisclosure to SARS-CoV-2.

“Fab” with regard to an antibody refers to that portion of the antibodyconsisting of a single light chain (both variable and constant regions)bound to the variable region and first constant region of a single heavychain by a disulfide bond. The heavy chain fragment of the Fab is knownas “Fd”.

“Fab′” refers to a Fab fragment that includes a portion of the hingeregion.

“F(ab′)₂” refers to a dimer of Fab′.

“Fc” with regard to an antibody (e.g. of IgG, IgA, or IgD isotype)refers to that portion of the antibody consisting of the second andthird constant domains of a first heavy chain bound to the second andthird constant domains of a second heavy chain via disulfide bonding. Fcwith regard to antibody of IgM and IgE isotype further comprises afourth constant domain. The Fc portion of the antibody is responsiblefor various effector functions such as antibody-dependent cell-mediatedcytotoxicity (ADCC), Antibody-dependent cellular phagocytosis (ADCP) andcomplement dependent cytotoxicity (CDC), but does not function inantigen binding.

“Fv” with regard to an antibody refers to the smallest fragment of theantibody to bear the complete antigen binding site. An Fv fragmentconsists of the variable region of a single light chain bound to thevariable region of a single heavy chain.

“Single-chain Fv antibody” or “scFv” refers to an engineered antibodyconsisting of a light chain variable region and a heavy chain variableregion connected to one another directly or via a peptide linkersequence (Huston J S et al. Proc Natl Acad Sci USA, 85:5879(1988)).

“ScFab” refers to a fusion polypeptide with a Fd linked to a light chainvia a polypeptide linker, resulting in the formation of a single chainFab fragment (scFab).

“Single-chain Fv-Fc antibody” or “scFv-Fc” refers to an engineeredantibody consisting of a scFv connected to the Fc region of an antibody.

“Camelized single domain antibody,” “heavy chain antibody,” or “HCAb”refers to an antibody that contains two V_(H) domains and no lightchains (Riechmann L. and Muyldermans S., J Immunol Methods. December 10;231(1-2):25-38 (1999); Muyldermans S., J Biotechnol. June; 74(4):277-302(2001); WO94/04678; WO94/25591; U.S. Pat. No. 6,005,079). Heavy chainantibodies were originally derived from Camelidae (camels, dromedaries,and llamas). Although devoid of light chains, camelized antibodies havean authentic antigen-binding repertoire (Hamers-Casterman C. et al.,Nature. June 3; 363(6428):446-8 (1993); Nguyen V K. et al.Immunogenetics. April; 54(1):39-47 (2002); Nguyen V K. et al.Immunology. May; 109(1):93-101 (2003)). The variable domain of a heavychain antibody (VHH domain) represents the smallest knownantigen-binding unit generated by adaptive immune responses (Koch-NolteF. et al., FASEB J. November; 21(13):3490-8. Epub 2007 Jun. 15 (2007)).

A “nanobody” refers to an antibody fragment that consists of a VHHdomain from a heavy chain antibody and two constant domains, CH2 andCH3.

A “domain antibody” refers to an antibody fragment containing only thevariable region of a heavy chain or the variable region of a lightchain. In certain instances, two or more VH domains are covalentlyjoined with a peptide linker to create a bivalent or multivalent domainantibody. The two VH domains of a bivalent domain antibody may targetthe same or different antigens.

The term “valent” as used herein refers to the presence of a specifiednumber of antigen binding sites in a given molecule. The term“monovalent” refers to an antibody or an antigen-binding fragment havingonly one single antigen-binding site; and the term “multivalent” refersto an antibody or an antigen-binding fragment having multipleantigen-binding sites. As such, the terms “bivalent”, “tetravalent”, and“hexavalent” denote the presence of two binding sites, four bindingsites, and six binding sites, respectively, in an antigen-bindingmolecule. In some embodiments, the antibody or antigen-binding fragmentthereof is bivalent.

“TriFabs” refers to a trivalent, bispecific fusion protein composed ofthree units with Fab-functionalities. TriFabs harbor two regular Fabsfused to an asymmetric Fab-like moiety.

“Fab-Fab” refers to a fusion protein formed by fusing the Fd chain of afirst Fab arm to the N-terminus of the Fd chain of a second Fab arm.

“Fab-Fv” refers to a fusion protein formed by fusing a heavy chainvariable domain to the C-terminus of an Fd chain and a light chainvariable domain to the C-terminus of a light chain. A “Fab-dsFv”molecule can be formed by introducing an interdomain disulphide bondbetween the heavy chain variable domain and the heavy chain variabledomain.

An “scFv dimer” is a bivalent diabody or bispecific scFv (BsFv)comprising V_(H)-V_(L) (linked by a peptide linker) dimerized withanother V_(H)-V_(L) moiety such that V_(H)'s of one moiety coordinatewith the V_(L)'s of the other moiety and form two binding sites whichcan target the same antigens (or epitopes) or different antigens (orepitopes).

A bispecific “scFv dimer” is a bispecific diabody comprisingV_(H1)-V_(L2) (linked by a peptide linker) associated with V_(L1)-V_(H2)(also linked by a peptide linker) such that V_(H1) and V_(L1) coordinateand V_(H2) and V_(L2) coordinate and each coordinated pair has adifferent antigen specificity.

A “dsFv” refers to a disulfide-stabilized Fv fragment that the linkagebetween the variable region of a single light chain and the variableregion of a single heavy chain is a disulfide bond. In some embodiments,a “(dsFv)₂” or “(dsFv-dsFv′)” comprises three peptide chains: two V_(H)moieties linked by a peptide linker (e.g. a long flexible linker) andbound to two V_(L) moieties, respectively, via disulfide bridges. Insome embodiments, dsFv-dsFv′ is bispecific in which each disulfidepaired heavy and light chain has a different antigen specificity.

“Bibody” refers to a fusion protein formed by fusing a scFv to theC-terminus of either the light chain (Fab-L-scFv) or Fd (Fab-H-scFv).

“Tribody” refers to a fusion protein formed by fusing a scFv to bothlight chain and heavy chain (Fab-(scFv)₂).

“MAb-Fv” or “IgG-Fv” refers to a fusion protein formed by fusion ofheavy chain variable domain (VH domain) to the C-terminus of one Fcchain and the VL domain either expressed separately or fused to theC-terminus of the other resulted in a bispecific, trivalent IgG-Fv(mAb-Fv) fusion protein, with the Fv stabilized by an interdomaindisulphide bond.

“ScFab-Fc-scFv₂” and “ScFab-Fc-scFv” refer to a fusion protein formed byfusion of a single-chain Fab with Fc and disulphide-stabilized Fvdomains.

“Appended IgG” refers to a fusion protein with a Fab arm fused to an IgGto form the format of bispecific (Fab)₂-Fc. It can form an “IgG-Fab” ora “Fab-IgG”, with a Fab fused to the C-terminus or N-terminus of an IgGmolecule with or without a connector. In certain embodiments, theappended IgG can be further modified to a format of IgG-Fab₄ (see,Brinkman et al., mAbs, 9(2), pp.182-212 (2017)).

“DVD-Ig” refers to a dual-variable-domain antibody that is formed byfusion of an additional VH domain and VL domain of a second specificityto an IgG heavy chain and light chain. “CODV-Ig” refers to a relatedformat where the two VH domain and two VL domains are linked in a waythat allows crossover pairing of the variable VH domain-VL domain, whichare arranged either (from N- to C-terminus) in the order VH domain A-VHdomain B and VL domain B-VL domain A, or in the order VH domain B-VHdomain A and VL domain A-VL domain B.

A “CrossMab” refers to a technology of pairing of unmodified light chainwith the corresponding unmodified heavy chain and pairing of themodified light chain with the corresponding modified heavy chain, thusresulting an antibody with reduced mispairing in the light chain.

A “WuxiBody” refers to is a bispecific antibody comprising a chimericprotein with variable domains of an antibody and the constant domains ofTCR, wherein the subunits (such as alpha and beta domains) of TCRconstant domains are associated by engineered disulfide bond (see, moredetails in WO2019057122A1).

A “BiTE” is a bispecific T-cell engager molecule, comprising a firstscFv with a first antigen specificity in the VL domain-VH domainorientation linked to a second scFv with a second specificity in the VHdomain-VL domain orientation.

A “diabody” or “dAb” includes small antibody fragments with twoantigen-binding sites, wherein the fragments comprise a V_(H) domainconnected to a V_(L) domain in the same polypeptide chain (V_(H)-V_(L)or VL-VH) (see, e.g. Holliger P. et al., Proc Natl Acad Sci USA. July15; 90(14):6444-8 (1993); EP404097; WO93/11161). By using a linker thatis too short to allow pairing between the two domains on the same chain,the domains are forced to pair with the complementary domains of anotherchain, thereby creating two antigen-binding sites. The antigen-bindingsites may target the same or different antigens (or epitopes).

A “DART” is a diabody-like entity that has the VH of a first variableregion linked to the VL of a second variable region, and the VH of thesecond variable region linked to the VL of the first variable region.

A “TandAb” is a bispecific fusion protein with four binding sites, twoof which bind to a first antigen and the other two bind to a secondantigen.

A “bispecific ds diabody” is a diabody target two different antigens (orepitopes).

The term “fully human” when used with reference to an antibody, refersto an antibody that are either directly derived from a human or basedupon a human sequence. When an antibody is derived from or based on ahuman sequence and subsequently modified, it is still to be consideredfully human as used throughout the specification. In other words, theterm “fully human” when used with reference to an antibody, is intendedto include binding molecules having variable and constant regionsderived from human germline immunoglobulin sequences or based onvariable or constant regions occurring in a human or human lymphocyteand modified in some form. Thus, the fully human antibody may includeamino acid residues not encoded by human germline immunoglobulinsequences, comprise substitutions and/or deletions (e.g., mutationsintroduced by, for instance, random or site-specific mutagenesis invitro or by somatic mutation in vivo). “Based on” as used herein refersto the situation that a nucleic acid sequence may be exactly copied froma template, or with minor mutations, such as by error-prone PCR methods,or synthetically made matching the template exactly or with minormodifications. Semi-synthetic molecules based on human sequences arealso considered to be human as used herein.

Other Terms

The term “affinity” as used herein refers to the strength ofnon-covalent interaction between an immunoglobulin molecule (i.e.antibody) or fragment thereof and an antigen.

The term “amino acid” as used herein refers to an organic compoundcontaining amine (—NH₂) and carboxyl (—COOH) functional groups, alongwith a side chain specific to each amino acid. The names of amino acidsare also represented as standard single letter or three-letter codes inthe present disclosure, which are summarized as follows.

Three- Single- Name of Amino letter letter Acid Code Code Alanine Ala AArginine Arg R Asparagine Asn N Aspartic acid Asp D Cysteine Cys CGlutamic acid Glu E Glutamine Gln Q Glycine Gly G Histidine His HIsoleucine Ile I Leucine Leu L Lysine Lys K Methionine Met MPhenylalanine Phe F Proline Pro P Serine Ser S Threonine Thr TTryptophan Trp W Tyrosine Tyr Y Valine Val V

A “conservative substitution” with reference to amino acid sequencerefers to replacing an amino acid residue with a different amino acidresidue having a side chain with similar physiochemical properties. Forexample, conservative substitutions can be made among amino acidresidues with hydrophobic side chains (e.g. Met, Ala, Val, Leu, andIle), among residues with neutral hydrophilic side chains (e.g. Cys,Ser, Thr, Asn and Gln), among residues with acidic side chains (e.g.Asp, Glu), among amino acids with basic side chains (e.g. His, Lys, andArg), or among residues with aromatic side chains (e.g. Trp, Tyr, andPhe). As known in the art, conservative substitution usually does notcause significant change in the protein conformational structure, andtherefore could retain the biological activity of a protein.

The term “diagnosis”, “diagnose” or “diagnosing” refers to theidentification of a pathological state, disease or condition, such asidentification of SARS-CoV-2 infection, or refer to identification of asubject with SARS-CoV-2 infection who may benefit from a particulartreatment regimen. In some embodiments, diagnosis contains theidentification of presence or amount of SARS-CoV-2. In some embodiments,diagnosis refers to the identification of SARS-CoV-2 infection in asubject.

“Effector functions” as used herein refer to biological activitiesattributable to the binding of Fc region of an antibody to its effectorssuch as C1 complex and Fc receptor. Exemplary effector functionsinclude: complement dependent cytotoxicity (CDC) mediated by interactionof antibodies and C1q on the C1 complex; antibody-dependentcell-mediated cytotoxicity (ADCC) mediated by binding of Fc region of anantibody to Fc receptor on an effector cell; and phagocytosis. Effectorfunctions can be evaluated using various assays such as Fc receptorbinding assay, C1q binding assay, and cell lysis assay.

The term “Antibody-dependent cell-mediated cytotoxicity” and “ADCC”refer to a cell-mediated reaction in which nonspecific cytotoxic cellsthat express FcRs (e.g. Natural Killer (NK) cells, neutrophils, andmacrophages) recognize bound antibody on a target ceil and subsequentlycause lysis of the target cell. The primary cells for mediating ADCC, NKcells, express FcγRIII only, whereas monocytes express FcγRI, FcγRII andFcγRIII. FcR expression on hematopoietic cells is summarized in Table 3on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991).

The term “specific binding” or “specifically binds” in reference to theinteraction of a binding molecule, e.g., an antibody, and its bindingpartner, e.g., an antigen, means that the interaction is dependent uponthe presence of a particular structure, e.g., an antigenic determinantor epitope, on the binding partner. In other words, the antibodypreferentially binds or recognizes the binding partner even when thebinding partner is present in a mixture of other molecules or organisms.The binding may be mediated by covalent or non-covalent interactions ora combination of both. Antibodies or fragments thereof thatimmunospecifically bind to an antigen may be cross-reactive with relatedantigens, carrying the same epitope. Specific binding can becharacterized in binding affinity, for example, represented by K_(d)value, i.e., the dissociation constant between the antigen andantigen-binding molecule. K_(d) may be determined by using anyconventional method known in the art, including but are not limited toradioimmunoassays (RIA), enzyme-linked immunosorbent assays (ELISA),surface plasmon resonance method, microscale thermophoresis method,HPLC-MS method and flow cytometry (such as FACS) method. A K_(d) valueof

10⁻⁶ M (e.g.

5×10⁻⁷ M,

2×10⁻⁷ M,

10⁻⁷ M,

5×10⁻⁸ M,

2×10⁻⁸ M,

10⁻⁸ M,

5×10⁻⁹ M,

4×10⁻⁹M,

3×10⁻⁹M,

2×10⁻⁹ M, or

10⁻⁹ M) can indicate specific binding between an antibody or antigenbinding fragments thereof and SARS-CoV-2 (e.g. spike protein ofSARS-CoV-2, or receptor binding domain of the spike protein ofSARS-CoV-2).

The ability to “compete for binding to RBD” as used herein refers to theability of a SARS-CoV-2 antibody or antigen-binding fragment thereof toinhibit the binding interaction between RBD of spike protein ofSARS-CoV-2 and its binding partner (e.g. a second SARS-CoV-2 antibody,or ACE2 receptor) to any detectable degree. In certain embodiments, anantibody or antigen-binding fragment that compete for binding toSARS-CoV-2 inhibits the binding interaction between RBD of spike proteinof SARS-CoV-2 and its binding partner by at least 85%, or at least 90%.In certain embodiments, this inhibition may be greater than 95%, orgreater than 99%. In general, competitive inhibition is measured bymeans of an assay, wherein an antigen composition, i.e., a compositioncomprising SARS-CoV-2 or fragments thereof, is admixed with referencebinding molecules, for example, the antibodies or antigen bindingfragments of the present disclosure, or the ACE receptor (e.g. arecombinant binding moiety thereof), and the antibodies or antigenbinding fragments to be screened. Usually, the antibodies or antigenbinding fragments to be screened are present in excess. Protocols basedupon ELISAs and Western blotting are suitable for use in such simplecompetition studies.

In certain embodiments, an antibody or antigen-binding fragment exhibitsat least 30% competition at 1 μM, with 2 μM angiotensin convertingenzyme 2 (ACE2) receptor for binding to the RBD of spike protein ofSARS-CoV-2 immobilized at a resonance units (RU) of 250, as measured bySPR.

The term “homologous” as used herein refers to nucleic acid sequences(or its complementary strand) or amino acid sequences that have sequenceidentity of at least 60% (e.g. at least 65%, 70%, 75%, 80%, 85%, 88%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%) to another sequenceswhen optimally aligned.

The phrase “host cell” as used herein refers to a cell into which anexogenous polynucleotide and/or a vector can be or has been introduced.

The term “isolated” means one substance has been altered by the hand ofman from the natural state. If an “isolated” composition or substanceoccurs in nature, it has been changed or removed from its originalenvironment, or both. For example, a polynucleotide or a polypeptidenaturally present in a living animal is not “isolated,” but the samepolynucleotide or polypeptide is “isolated” if it has been sufficientlyseparated from the coexisting materials of its natural state so as toexist in a substantially pure state. An “isolated nucleic acid sequence”refers to the sequence of an isolated nucleic acid molecule. In certainembodiments, an “isolated antibody or an antigen-binding fragmentthereof” refers to the antibody or antigen-binding fragments thereofhaving a purity of at least 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% asdetermined by electrophoretic methods (such as SDS-PAGE, isoelectricfocusing, capillary electrophoresis), or chromatographic methods (suchas ion exchange chromatography or reverse phase HPLC). In someembodiment, an isolated antibody or antigen binding fragment is arecombinant protein or antigen binding fragment.

The term “modified antibody”, “modified antibodies”, or a grammaticvariation as used herein refers to an antibody that has been modified,bioengineered, or combined with one or more modification elements so itis not a naturally occurring antibody.

The term “kit” as used herein refers to a packaged combination ofreagents in predetermined amounts with instructions for performing atherapeutics, or a diagnostic or detection assay.

The term “neutralizing” as used herein in relation to the antibody orthe antigen binding fragment of the present disclosure refers toantibody or the antigen binding fragment that inhibit SARS-CoV-2 virusfrom infecting a target cell for replication, regardless of themechanism by which neutralization is achieved. Thus, neutralization can,for example, be achieved by inhibiting the attachment or adhesion ofSARS-CoV-2 virus or a pseudo SARS-CoV-2 virus bearing the spike proteinto the cell surface, or by inhibition of the fusion of viral andcellular membranes following attachment of the virus to the target cell,and the like. Exemplary assays for determining neutralizing activity aredescribed in the Examples provided herein.

In some embodiments, the neutralizing activity of an antibody can berepresented as half-maximal inhibitory concentrations (IC₅₀) of theantibody against the binding to ACE2.

The term “nucleic acid” or “polynucleotide” as used herein refers todeoxyribonucleic acids (DNA) or ribonucleic acids (RNA) and polymersthereof in either single- or double-stranded form. Unless otherwiseindicated, a particular polynucleotide sequence also implicitlyencompasses conservatively modified variants thereof (e.g. degeneratecodon substitutions), alleles, orthologs, SNPs, and complementarysequences as well as the sequence explicitly indicated. Specifically,degenerate codon substitutions may be achieved by generating sequencesin which the third position of one or more selected (or all) codons issubstituted with mixed-base and/or deoxyinosine residues (see Batzer etal., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem.260:2605-2608 (1985); and Rossolini et al., Mol. Cell. Probes 8:91-98(1994)).

“Percent (%) sequence identity” with respect to amino acid sequence (ornucleic acid sequence) is defined as the percentage of amino acid (ornucleic acid) residues in a candidate sequence that are identical to theamino acid (or nucleic acid) residues in a reference sequence, afteraligning the sequences and, if necessary, introducing gaps, to achievethe maximum number of identical amino acids (or nucleic acids).Conservative substitution of the amino acid residues may or may not beconsidered as identical residues. Alignment for purposes of determiningpercent amino acid (or nucleic acid) sequence identity can be achieved,for example, using publicly available tools such as BLASTN, BLASTp(available on the website of U.S. National Center for BiotechnologyInformation (NCBI), see also, Altschul S. F. et al., J. Mol. Biol.,215:403-410 (1990); Stephen F. et al., Nucleic Acids Res., 25:3389-3402(1997)), ClustalW2 (available on the website of European BioinformaticsInstitute, see also, Higgins D. G. et al., Methods in Enzymology,266:383-402 (1996); Larkin M. A. et al., Bioinformatics (Oxford,England), 23(21): 2947-8 (2007)), and ALIGN or Megalign (DNASTAR)software. A person skilled in the art may use the default parametersprovided by the tool, or may customize the parameters as appropriate forthe alignment, such as for example, by selecting a suitable algorithm.

The term “polypeptide” or “protein” means a string of at least two aminoacids linked to one another by peptide bonds. Polypeptides and proteinsmay include moieties in addition to amino acids (e.g., may beglycosylated) and/or may be otherwise processed or modified. Those ofordinary skill in the art will appreciate that a “polypeptide” or“protein” can be a complete polypeptide chain as produced by a cell(with or without a signal sequence), or can be a functional portionthereof. Those of ordinary skill will further appreciate that apolypeptide or protein can sometimes include more than one polypeptidechain, for example linked by one or more disulfide bonds or associatedby other means. The term also includes amino acid polymers in which oneor more amino acids are chemical analogs of a correspondingnaturally-occurring amino acid and polymers.

The term “pharmaceutically acceptable” indicates that the designatedcarrier, vehicle, diluent, excipient(s), and/or salt is generallychemically and/or physically compatible with the other ingredientscomprising the formulation, and physiologically compatible with therecipient thereof.

The term “recombinant” when used with reference to a polypeptide (e.g.,antibody, antigen) or a polynucleotide, refers to a polypeptide orpolynucleotide that is produced by a recombinant method. A “recombinantpolypeptide” includes any polypeptide expressed from a recombinantpolynucleotide. A “recombinant polynucleotide” includes anypolynucleotide which has been modified by the introduction of at leastone exogenous (i.e., foreign, and typically heterologous) nucleotide orthe alteration of at least one native nucleotide component of thepolynucleotide, and need not include all of the coding sequence or theregulatory elements naturally associated with the coding sequence. A“recombinant vector” refers to a non-naturally occurring vector,including, e.g., a vector comprising a recombinant polynucleotidesequence.

As used herein, the term “sample” refers to a biological specimen thatis obtained or derived from a subject of interest. The sample contains acellular and/or other molecular entity that is to be characterizedand/or identified, for example based on physical, biochemical, chemicaland/or physiological characteristics.

The term “subject” includes human and non-human animals. Non-humananimals include all vertebrates, e.g., mammals and non-mammals, such asnon-human primates, mice, rats, cats, rabbits, sheep, dogs, cows,chickens, amphibians, and reptiles. Except when noted, the terms“patient” or “subject” are used herein interchangeably.

The term “treating” or “treatment” of a disease, disorder or conditionas used herein includes alleviating a disease, disorder or condition,slowing the rate of development of a disease, disorder or condition,reducing or ending symptoms associated with a disease, disorder orcondition, generating a complete or partial regression of a disease,disorder or condition, curing a disease, disorder or condition, or somecombination thereof.

The term “prevent” or “preventing” of a disease, disorder or conditionas used herein includes slowing the onset of a disease, disorder orcondition, reducing the risk of developing a disease, disorder orcondition, preventing or delaying the development of symptoms associatedwith a disease, disorder or condition, reducing the severity of asubsequent contraction or development of a disease, disorder orcondition, ameliorating a related symptom, and inducing immunity toprotect against a disease, disorder or condition.

The term “SARS-CoV-2 virus antigen” as used herein refers to aSARS-CoV-2 virus particle or an antigen found in a SARS-CoV-2 virusparticle (e.g. a protein or protein fragments of envelop protein orspike protein (includes, extracellular domain of the spike protein, orRBD of the spike protein) and the like). Spike protein is composed of S1protein (which contains RBD) and S2 protein, which are initially in oneprotein molecule until cleaved by protease into S1 and S2.

The term “vector” as used herein refers to a vehicle into which agenetic element may be operably inserted so as to bring about theexpression of that genetic element, such as to produce the protein, RNAor DNA encoded by the genetic element, or to replicate the geneticelement. A vector may be used to transform, transduce, or transfect ahost cell so as to bring about expression of the genetic element itcarries within the host cell. Examples of vectors include plasmids,phagemids, cosmids, artificial chromosomes such as yeast artificialchromosome (YAC), bacterial artificial chromosome (BAC), or P1-derivedartificial chromosome (PAC), bacteriophages such as lambda phage or M13phage, and animal viruses. A vector may contain a variety of elementsfor controlling expression, including promoter sequences, transcriptioninitiation sequences, enhancer sequences, selectable elements, andreporter genes. In addition, the vector may contain an origin ofreplication. A vector may also include materials to aid in its entryinto the cell, including but not limited to a viral particle, aliposome, or a protein coating. A vector can be an expression vector ora cloning vector. The present disclosure provides vectors (e.g.expression vectors) containing the nucleic acid sequence provided hereinencoding the antibody or an antigen-binding fragment thereof, at leastone promoter (e.g. SV40, CMV, EF-1α) operably linked to the nucleic acidsequence, and at least one selection marker.

Anti-SARS-CoV-2 Antibodies

The present disclosure in one aspect provides anti-SARS-CoV-2 antibodiesand antigen-binding fragments thereof.

In some embodiments, the disclosure is directed to a modified antibodyor an antigen-binding fragment thereof comprising at least anantigen-binding domain having an antigen-binding affinity and acovalently linked modified human IgG constant domain, wherein theantigen-binding affinity comprises SARS-CoV-2 binding affinity, theantigen-binding affinity comprises at least 50% less or non-detectablebinding affinity to SARS-CoV or MERS-CoV compared to the SARS-CoV-2binding affinity, and wherein the modified human IgG constant domaincomprises a substitution with tyrosine at amino acid residue 252, asubstitution with threonine at amino acid residue 254, and asubstitution with glutamic acid at amino acid residue 256, numberedaccording to the EU index as in Kabat, the modified antibody has anincreased affinity for FcRn compared to the affinity to FcRn of anantibody having a wild type human IgG constant domain.

The modified human IgG constant domain comprises a substitution withtyrosine at amino acid residue 252, a substitution with threonine atamino acid residue 254, and a substitution with glutamic acid at aminoacid residue 256, numbered according to the EU index as in Kabat, can bereferred to YTE domain or YTE domain Fc.

In some cases, the antigen-binding affinity can comprise:

a) binding affinity to spike protein of SARS-CoV-2 with at least 50%less binding to spike protein of SARS-CoV or spike protein of MERS-CoV;

b) binding affinity to receptor-binding domain (RBD) of the spikeprotein of SARS-CoV-2 comprising the amino acid sequence of SEQ ID NO:128;

c) binding affinity to RBD of said spike protein of SARS-CoV comprisingthe amino acid sequence of SEQ ID NO: 124 at a level that isnon-detectable or that is no more than 50% of said binding affinity tosaid RBD of said spike protein of SARS-CoV-2;

d) binding affinity to RBD of said spike protein of MERS-CoV comprisingthe amino acid sequence of SEQ ID NO: 126 at a level that isnon-detectable or that is no more than 50% of said binding affinity tosaid RBD of the spike protein of SARS-CoV-2;

e) binding affinity to said RBD of said spike protein of SARS-CoV-2 at aKd value of no more than 1×10⁻⁷M as measured by Surface PlasmonResonance (SPR);

f) binding affinity to said RBD of said spike protein of SARS-CoV or theRBD of spike protein of MERS-CoV at a Kd value of at least 1×10⁻⁶M asmeasured by SPR;

g) exhibiting at least 30% competition at 104, with 2 μM angiotensinconverting enzyme 2 (ACE2) receptor, for binding to said RBD of saidspike protein of SARS-CoV-2 immobilized at a resonance unit (RU) of 250,as measured by SPR;

h) binding affinity to said RBD of said spike protein of SARS-CoV-2 at aneutralizing activity at an IC50 value of no more than 100 μg/ml (forexample, no more than 50 μg/ml, no more than 40 μg/ml, no more than 30μg/ml, no more than 25 μg/ml, no more than 20 μg/ml, no more than 15μg/ml, no more than 10 μg/ml, no more than 8 μg/ml, no more than 6μg/ml, no more than 4 μg/ml, no more than 2 μg/ml, or no more than 1μg/ml), as measured by pseudovirus, live virus microneutralization,inactivated virus neutralization assay, or a combination thereof;

i) capable of binding to the RBD of spike protein of SARS-CoV-2 at anneutralizing activity at an IC₅₀ value of no more than 1 μg/ml (forexample, no more than 50 ng/ml, no more than 40 ng/ml, no more than 30ng/ml, no more than 25 ng/ml, no more than 20 ng/ml, no more than 15ng/ml, no more than 10 ng/ml, no more than 8 ng/ml, no more than 6ng/ml, no more than 4 ng/ml, no more than 2 ng/ml, or no more than 1ng/ml), as measured by live virus neutralization assay using focusreduction neutralization test (FRNT) method or

a combination thereof.

In some cases, the antigen-binding affinity can be selected from thegroup consisting of:

a) binding affinity to spike protein of SARS-CoV-2 with at least 50%less binding to spike protein of SARS-CoV or spike protein of MERS-CoV;

b) binding affinity to receptor-binding domain (RBD) of the spikeprotein of SARS-CoV-2 comprising the amino acid sequence of SEQ ID NO:128;

c) binding affinity to RBD of said spike protein of SARS-CoV comprisingthe amino acid sequence of SEQ ID NO: 124 at a level that isnon-detectable or that is no more than 50% of said binding affinity tosaid RBD of said spike protein of SARS-CoV-2;

d) binding affinity to RBD of said spike protein of MERS-CoV comprisingthe amino acid sequence of SEQ ID NO: 126 at a level that isnon-detectable or that is no more than 50% of said binding affinity tosaid RBD of the spike protein of SARS-CoV-2;

e) binding affinity to said RBD of said spike protein of SARS-CoV-2 at aKd value of no more than 1×10-7M as measured by Surface PlasmonResonance (SPR);

f) binding affinity to said RBD of said spike protein of SARS-CoV or theRBD of spike protein of MERS-CoV at a Kd value of at least 1×10-6M asmeasured by SPR;

g) exhibiting at least 30% competition at 1 μM, with 2 μM angiotensinconverting enzyme 2 (ACE2) receptor, for binding to said RBD of saidspike protein of SARS-CoV-2 immobilized at a resonance unit (RU) of 250,as measured by SPR;

h) binding affinity to said RBD of said spike protein of SARS-CoV-2 at aneutralizing activity at an IC50 value of no more than 100 μg/ml, asmeasured by pseudovirus, live virus microneutralization, inactivatedvirus neutralization assay, or a combination thereof;

i) capable of binding to the RBD of spike protein of SARS-CoV-2 at anneutralizing activity at an IC₅₀ value of no more than 1 μg/ml (forexample, no more than 50 ng/ml, no more than 40 ng/ml, no more than 30ng/ml, no more than 25 ng/ml, no more than 20 ng/ml, no more than 15ng/ml, no more than 10 ng/ml, no more than 8 ng/ml, no more than 6ng/ml, no more than 4 ng/ml, no more than 2 ng/ml, or no more than 1ng/ml), as measured by live virus neutralization assay using focusreduction neutralization test (FRNT) method;

and a combination thereof.

In some embodiments, the anti-SARS-CoV-2 antibodies and antigen-bindingfragments provided herein are capable of specifically binding toSARS-CoV-2. In certain embodiments, the antibodies and theantigen-binding fragments thereof provided herein specifically bind toSARS-CoV-2 at an Kd value of no more than 10⁻⁷ M as measured by SPR.

In certain embodiments, the antibodies and the antigen-binding fragmentsthereof provided herein are capable of binding to the RBD of spikeprotein of SARS-CoV-2 at a Kd value of no more than 1×10⁻⁷M (e.g. nomore than 5×10⁻⁷ M, no more than 2×10⁻⁷ M, no more than 10⁻⁷ M, no morethan 5×10⁻⁸ M, no more than 2×10⁻⁸ M, no more than 10⁻⁸ M, no more than5×10⁻⁹ M, no more than 4×10⁻⁹M, no more than 3×10⁻⁹M, no more than2×10⁻⁹ M, or no more than 10⁻⁹ M) as measured by SPR.

In certain embodiments, the antibodies and the antigen-binding fragmentsthereof provided herein bind to the RBD of spike protein of SARS-CoV orthe RBD of spike protein of MERS-CoV at a significantly lower affinityor degree. In certain embodiments, the antibodies and theantigen-binding fragments thereof provided herein exhibit binding to theRBD of spike protein of SARS-CoV or the RBD of spike protein of MERS-CoVat a Kd value of at least 1×10⁻⁶M (e.g. at least 2×10⁻⁶ M, at least5×10⁻⁶ M, at least 10⁻⁵ M) as measured by SPR.

In certain embodiments, the antibodies and the antigen-binding fragmentsthereof provided herein do not detectably bind to SARS-CoV or MERS-CoV.In certain embodiments, the antibodies and the antigen-binding fragmentsthereof provided herein exhibits at least 50% (e.g., at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%) less binding or non-detectable binding toSARS-CoV or MERS-CoV, than the binding to SARS-CoV-2 under equivalentassay conditions. In certain embodiments, the antibodies and theantigen-binding fragments thereof provided herein are capable ofspecifically binding to spike protein of SARS-CoV-2 and exhibiting atleast 50% (e.g., at least 55%, at least 60%, at least 65%, at least 70%,at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, atleast 96%, at least 97%, at least 98%, at least 99%) less binding tospike protein of SARS-CoV or spike protein of MERS-CoV, than the bindingto spike protein of SARS-CoV-2 under equivalent assay conditions. Incertain embodiments, the full length of spike protein of SARS-CoV-2 cancomprise an amino acid sequence of SEQ ID NO: 134, optionally encoded bya polynucleotide sequence of SEQ ID NO: 135. In certain embodiments, theantibodies and the antigen-binding fragments thereof provided herein arecapable of specifically binding to receptor-binding domain (RBD) of thespike protein of SARS-CoV-2 comprising the amino acid sequence of SEQ IDNO: 128. In certain embodiments, the antibodies and the antigen-bindingfragments thereof provided herein exhibit binding to RBD of spikeprotein of SARS-CoV comprising the amino acid sequence of SEQ ID NO: 124at a level that is non-detectable or that is no more than 50% (e.g., nomore than 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 2%, 1%) of thebinding to the RBD of spike protein of SARS-CoV-2 under equivalent assayconditions. In certain embodiments, the antibodies and theantigen-binding fragments thereof provided herein exhibit binding to RBDof spike protein of MERS-CoV comprising the amino acid sequence of SEQID NO: 126 at a level that is non-detectable or that is no more than 50%(e.g., no more than 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 2%, 1%)of the binding to RBD of the spike protein of SARS-CoV-2 underequivalent assay conditions.

In certain embodiments, the antibodies and the antigen-binding fragmentsthereof provided herein are capable of exhibiting at least 30%competition at 1 μM, with 2 μM ACE2 receptor for binding to the RBD ofspike protein of SARS-CoV-2 immobilized at a (RU of 250, as measured bySPR. For example, SARS-CoV-2 RBD can be immobilized to a CM5 sensor chipvia amine group for a final RU around 250. 1 μM of the antibodies or theantigen-binding fragments thereof provided herein can be injected ontothe chip until binding steady-state is reached. 2 μM of human ACE2 orhuman ACE2 peptidase domain can be injected for 60 seconds. Blockingefficacy can be determined by comparison of response units with andwithout the antibody incubation. Instruments and kits for SPR arecommercially available as, for example, Biacore T200, GE Healthcare.

In certain embodiments, the antibodies and the antigen-binding fragmentsthereof provided herein are capable of binding to the RBD of spikeprotein of SARS-CoV-2 at an neutralizing activity at an IC₅₀ value of nomore than 100 μg/ml (e.g., no more than 90 μg/ml, 80 μg/ml, 70 μg/ml, 60μg/ml, 50 μg/ml, 40 μg/ml, 30 μg/ml, 20 μg/ml, 10 μg/ml, 5 μg/ml, 2μg/ml, 1 μg/ml, 0.5 μg/ml, 0.2 μg/ml, 0.1 μg/ml, 0.05 μg/ml, 0.03μg/ml), as measured by pseudovirus neutralization assay. Pseudovirusneutralization assay are known in the art, and in general involvesgenerating a pseudovirus expressing a reporter gene and a viral proteinof interest (such as the full length spike protein of SARS-CoV-2 of SEQID NO: 134). The antibodies and the antigen-binding fragments thereofprovided herein can be incubated with the pseudovirus, and the titer ofthe pseudovirus can be determined via the report gene. IC₅₀ is theconcentration of the antibodies or the antigen-binding fragment thereofcan inhibit 50% of the pseudovirus titer in the assay.

Illustrative Anti-SARS-CoV-2 Antibodies

In certain embodiments, the present disclosure provides SARS-CoV-2antibodies and antigen-binding fragments thereof comprising one or more(e.g. 1, 2, 3, 4, 5, or 6) CDRs comprising the sequences selected fromthe group consisting of SEQ ID NO: 1-6, 11-16, 21-26, 31-36, 41-46,51-56, 65-70, 75-80, 85-90, 95-100, 105-110, 136-141, 146-151, 156-161,166-171, 176-181, 186-191, 196-201, 206-211, 216-221, 226-231, 236-241,246-251, 256-261, 266-271, 276-281, 286-291, 296-301, 306-311, 316-321,326-331, 336-341, 346-351, 356-361, 366-371, 376-381, 386-391, 396-401,406-411, 416-421, and 426-431.

Antibody “P2A-1A8” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 7, and a light chain variable region having the sequence of SEQID NO: 8.

Antibody “P2A-1A9” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 17, and a light chain variable region having the sequence of SEQID NO: 18.

Antibody “P2A-1A10” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 27, and a light chain variable region having the sequence of SEQID NO: 28.

Antibody “P2A-1B3” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 37, and a light chain variable region having the sequence of SEQID NO: 38.

Antibody “P2B-2F6” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 47, and a light chain variable region having the sequence of SEQID NO: 48.

Antibody “P2B-2G4” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 57, and a light chain variable region having the sequence of SEQID NO: 58.

Antibody “P2B-2G11” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 61, and a light chain variable region having the sequence of SEQID NO: 62.

Antibody “P2C-1A3” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 71, and a light chain variable region having the sequence of SEQID NO: 72.

Antibody “P2C-1C8” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 81, and a light chain variable region having the sequence of SEQID NO: 82.

Antibody “P2C-1C10” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 91, and a light chain variable region having the sequence of SEQID NO: 92.

Antibody “P2C-1D5” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 101, and a light chain variable region having the sequence of SEQID NO: 102.

Antibody “P2C-1F11” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 111, and a light chain variable region having the sequence of SEQID NO: 112.

Antibody “P2B-1G5” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 142, and a light chain variable region having the sequence of SEQID NO: 143.

Antibody “P2B-1A1” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 152, and a light chain variable region having the sequence of SEQID NO: 153.

Antibody “P2C-1D7” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 162, and a light chain variable region having the sequence of SEQID NO: 163.

Antibody “P2B-1A10” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 172, and a light chain variable region having the sequence of SEQID NO: 173.

Antibody “P2B-1D9” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 182, and a light chain variable region having the sequence of SEQID NO: 183.

Antibody “P2B-1E4” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 192, and a light chain variable region having the sequence of SEQID NO: 193.

Antibody “P2B-1G1” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 202, and a light chain variable region having the sequence of SEQID NO: 203.

Antibody “P4A-2D9” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 212, and a light chain variable region having the sequence of SEQID NO: 213.

Antibody “P5A-2G7” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 222, and a light chain variable region having the sequence of SEQID NO: 223.

Antibody “P5A-3C8” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 232, and a light chain variable region having the sequence of SEQID NO: 233.

Antibody “P5A-1D2” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 242, and a light chain variable region having the sequence of SEQID NO: 243.

Antibody “P5A-2F11” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 252, and a light chain variable region having the sequence of SEQID NO: 253.

Antibody “P5A-2E1” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 262, and a light chain variable region having the sequence of SEQID NO: 263.

Antibody “P5A-1C8” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 272, and a light chain variable region having the sequence of SEQID NO: 273.

Antibody “P1A-1C10” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 282, and a light chain variable region having the sequence of SEQID NO: 283.

Antibody “P4A-1H6” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 292, and a light chain variable region having the sequence of SEQID NO: 293.

Antibody “P4B-1F4” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 302, and a light chain variable region having the sequence of SEQID NO: 303.

Antibody “P5A-1B6” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 312, and a light chain variable region having the sequence of SEQID NO: 313.

Antibody “P5A-1B8” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 322, and a light chain variable region having the sequence of SEQID NO: 323.

Antibody “P5A-1B9” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 332, and a light chain variable region having the sequence of SEQID NO: 333.

Antibody “P5A-1D1” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 342, and a light chain variable region having the sequence of SEQID NO: 343.

Antibody “P5A-1D10” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 352, and a light chain variable region having the sequence of SEQID NO: 353.

Antibody “P5A-2D11” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 362, and a light chain variable region having the sequence of SEQID NO: 363.

Antibody “P5A-2G9” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 372, and a light chain variable region having the sequence of SEQID NO: 373.

Antibody “P5A-2H3” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 382, and a light chain variable region having the sequence of SEQID NO: 383.

Antibody “P5A-3A1” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 392, and a light chain variable region having the sequence of SEQID NO: 393.

Antibody “P5A-3A6” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 402, and a light chain variable region having the sequence of SEQID NO: 403.

Antibody “P5A-3B4” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 412, and a light chain variable region having the sequence of SEQID NO: 413.

Antibody “P5A-3C12” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 422, and a light chain variable region having the sequence of SEQID NO: 423.

Antibody “P22A-1D1” as used herein refers to a monoclonal fully humanantibody having a heavy chain variable region having the sequence of SEQID NO: 432, and a light chain variable region having the sequence of SEQID NO: 433.

Table 1 below shows the CDR amino acid sequences of antibodies P2A-1A8,P2A-1A9, P2B-2G11, P2A-1A10, P2A-1B3, P2B-2F6, P2B-2G4, P2C-1A3,P2C-1C8, P2C-1C10, P2C- 1D5, P2C-1F11, P2B-1G5, P2B-1A1, P2C-1D7,P2B-1A10, P2B-1D9, P2B-1E4, P2B-1G1, P4A-2D9, P5A-2G7, P5A-3C8, P5A-1D2,P5A-2F11, P5A-2E1, P5A-1C8, P1A-1C10, P4A- 1H6, P4B-1F4, P5A-1B6,P5A-1B8, P5A-1B9, P5A-1D1, P5A-1D10, P5A-2D11, P5A-2G9, P5A-2H3,P5A-3A1, P5A-3A6, P5A-3B4, P5A-3C12, and P22A-1D1.

TABLE 1 CDR amino acid sequences of 42 antibodies CDR1 CDR2 CDR3 P2A-1A8HCDR SEQ ID NO: 1 SEQ ID NO: 2 SEQ ID NO: 3 GFAFDDYA STWNSGTIAKLGGYSDYDYPR PGDHYYGLDV LCDR SEQ ID NO: 4 SEQ ID NO: 5 SEQ ID NO: 6SSDVGSYNL DVN RSYTDSNTYV P2A-1A9 HCDR SEQ ID NO: 11 SEQ ID NO: 12SEQ ID NO: 13 GFTFDDYA ISWNGGII AKVAGRGDYDYY YGMDV LCDR SEQ ID NO: 14SEQ ID NO: 15 SEQ ID NO: 16 SSNIGAGYD GNN QSYDSSLSGSV P2A-1A10 HCDRSEQ ID NO: 21 SEQ ID NO: 22 SEQ ID NO: 23 GYTFTGYY INPNSGGTARVPYCSSTSCHRD WYFDL LCDR SEQ ID NO: 24 SEQ ID NO: 25 SEQ ID NO: 26QSLLDSDDGNTY TLS MQRIEFPLT P2A-1B3 HCDR SEQ ID NO: 31 SEQ ID NO: 32SEQ ID NO: 33 GFSFNRYS ISASGNTI ARPAMVREGTYN WFDP LCDR SEQ ID NO: 34SEQ ID NO: 35 SEQ ID NO: 36 QSVSNDY YAS QQYGDSPPIT P2B-2F6 HCDRSEQ ID NO: 41 SEQ ID NO: 42 SEQ ID NO: 43 GYSISSGYY IYHSGSTARAVVGIVVVPAA GRRAFDI LCDR SEQ ID NO: 44 SEQ ID NO: 45 SEQ ID NO: 46SSDVGGYNY EVS SSYAGSNNLV P2B-2G4 HCDR SEQ ID NO: 51 SEQ ID NO: 52SEQ ID NO: 53 GFTFSSYG IWYDGSNK ARGAAMVWLDY LCDR SEQ ID NO: 54SEQ ID NO: 55 SEQ ID NO: 56 SSDVGGYNY DVS CSYAGSYTFVV P2B-2G11 HCDRSEQ ID NO: 11 SEQ ID NO: 12 SEQ ID NO: 13 GFTFDDYA ISWNGGII AKVAGRGDYDYYYGMDV LCDR SEQ ID NO: 14 SEQ ID NO: 15 SEQ ID NO: 16 SSNIGAGYD GNNQSYDSSLSGSV P2C-1A3 HCDR SEQ ID NO: 65 SEQ ID NO: 66 SEQ ID NO: 67GFTFSDYY ISSSGSTI ARDFSHQQLVPS LCDR SEQ ID NO: 68 SEQ ID NO: 69SEQ ID NO: 70 QGISSY AAS QQLNSYPLT P2C-1C8 HCDR SEQ ID NO: 75SEQ ID NO: 76 SEQ ID NO: 77 GFTFRSYG IWYDGSNK ARDIEIVVVNIDY LCDRSEQ ID NO: 78 SEQ ID NO: 79 SEQ ID NO: 80 QSLVYSDGNTY KVS MQGTHWPYTP2C-1C10 HCDR SEQ ID NO: 85 SEQ ID NO: 86 SEQ ID NO: 87 GGTFSSYAIIPIFGTA ARVVTGYYFDY LCDR SEQ ID NO: 88 SEQ ID NO: 89 SEQ ID NO: 90QSVSSY DAS QQRSNWPS P2C-1D5 HCDR SEQ ID NO: 95 SEQ ID NO: 96SEQ ID NO: 97 GFTFSSFA ISGSGGST AKDPDGSGSWYFD Y LCDR SEQ ID NO: 98SEQ ID NO: 99 SEQ ID NO: 100 NIGSKS YDS QVWDSSSDHEIV P2C-1F11 HCDRSEQ ID NO: 105 SEQ ID NO: 106 SEQ ID NO: 107 GITVSSNY IYSGGSTARDLVVYGMDV LCDR SEQ ID NO: 108 SEQ ID NO: 109 SEQ ID NO: 110 QSVSSSYGAS QQYGSSPT P2B-1G5 HCDR SEQ ID NO: 136 SEQ ID NO: 137 SEQ ID NO: 138GYTFTTYV INTNTGNP SCEITTLGGMDV LCDR SEQ ID NO: 139 SEQ ID NO: 140SEQ ID NO: 141 NIGSKS YDS QVWDSISDHRV P2B-1A1 HCDR SEQ ID NO: 146SEQ ID NO: 147 SEQ ID NO: 148 GGSISSYY IYYSGST ARLERDWPLDAFDI LCDRSEQ ID NO: 149 SEQ ID NO: 150 SEQ ID NO: 151 SSDVGGYNY DVS SSYTSNNTFAP2C-1D7 HCDR SEQ ID NO: 156 SEQ ID NO: 157 SEQ ID NO: 158 GFTVSSNYIYSGGST ARELYEVGATDY LCDR SEQ ID NO: 159 SEQ ID NO: 160 SEQ ID NO: 161QSLVYSDGNTY KVS MQRYTLAGV P2B-1A10 HCDR SEQ ID NO: 166 SEQ ID NO: 167SEQ ID NO: 168 GFTVSSNY IYSGGST AREGPKSITGTAFDI LCDR SEQ ID NO: 169SEQ ID NO: 170 SEQ ID NO: 171 QDISNY DAS QQYDNLPMYT P2B-1D9 HCDRSEQ ID NO: 176 SEQ ID NO: 177 SEQ ID NO: 178 GFSLSTSGVG IYWDDDKAHTRILYYGSGSYY DY LCDR SEQ ID NO: 179 SEQ ID NO: 180 SEQ ID NO: 181SSNIGSNY SNN AAWDDSLSGVV P2B-1E4 HCDR SEQ ID NO: 186 SEQ ID NO: 187SEQ ID NO: 188 GFSLSTSGVG IYWDDDK AHQIVATIIDY LCDR SEQ ID NO: 189SEQ ID NO: 190 SEQ ID NO: 191 SSDVGGYNY DVS SSYTSSSVV P2B-1G1 HCDRSEQ ID NO: 196 SEQ ID NO: 197 SEQ ID NO: 198 GFTVSSNY IYSGGSTARDYGDYWFDP LCDR SEQ ID NO: 199 SEQ ID NO: 200 SEQ ID NO: 201 QSVSSSYGAS QQYGSSPRT P4A-2D9 HCDR SEQ ID NO: 206 SEQ ID NO: 207 SEQ ID NO: 208GFTFSSYG ISDDGSNQ AKRGGYCSTTSCL VRWVYFDY LCDR SEQ ID NO: 209SEQ ID NO: 210 SEQ ID NO: 211 QFISSY ATS QQSYNTLT PSA-2G7 HCDRSEQ ID NO: 216 SEQ ID NO: 217 SEQ ID NO: 218 GDSVSSGSYY IYYSGSTARERCYYGSGRAP RCVWFDP LCDR SEQ ID NO: 219 SEQ ID NO: 220 SEQ ID NO: 221SSDVGGYNY DVS SSYTSSSTLVV P5A-3C8 HCDR SEQ ID NO: 226 SEQ ID NO: 227SEQ ID NO: 228 GFTVSSNY IYSGGST ARDLQEHGMDV LCDR SEQ ID NO: 229SEQ ID NO: 230 SEQ ID NO: 231 QGISSY AAS QHLNSYPPGYT P5A-1D2 HCDRSEQ ID NO: 236 SEQ ID NO: 237 SEQ ID NO: 238 GFIVSSNY IYSGGSTARALQVGATSDYF DY LCDR SEQ ID NO: 239 SEQ ID NO: 240 SEQ ID NO: 241SSNIGAGYD GNS QSCDSSLSVVV P5A-2F11 HCDR SEQ ID NO: 246 SEQ ID NO: 247SEQ ID NO: 248 GYTFTSYD MNPNSGNT ARYIVVVPAAKGF DP LCDR SEQ ID NO: 249SEQ ID NO: 250 SEQ ID NO: 251 QSVLYSSNNKNY WAS QQYYSTPLT P5A-2E1 HCDRSEQ ID NO: 256 SEQ ID NO: 257 SEQ ID NO: 258 GYSFTSYW IYPGDSDTAQTSVTRNWFDP LCDR SEQ ID NO: 259 SEQ ID NO: 260 SEQ ID NO: 261 NIGSKSYDS QVWDSSSDHVV P5A-1C8 HCDR SEQ ID NO: 266 SEQ ID NO: 267SEQ ID NO: 268 GYTFTSYY INPSGGST ARSARDYYDSSGY YYRAEYFQH LCDRSEQ ID NO: 269 SEQ ID NO: 270 SEQ ID NO: 271 QDISNY DAS QQYDNLPSITP1A-1C10 HCDR SEQ ID NO: 276 SEQ ID NO: 277 SEQ ID NO: 278 GGTSSFYDIIPRLDIA ARGRPGSEWAYGP FDL LCDR SEQ ID NO: 279 SEQ ID NO: 280SEQ ID NO: 281 QSSRAW KAS HQYNSSPFT P4A-1H6 HCDR SEQ ID NO: 286SEQ ID NO: 287 SEQ ID NO: 288 GFTFSSYG ISDDGSNQ AKRGGYCSTTSCLL RWVYFDFLCDR SEQ ID NO: 289 SEQ ID NO: 290 SEQ ID NO: 291 QSISSY AAS QQSYNTPTP4B-1F4 HCDR SEQ ID NO: 296 SEQ ID NO: 297 SEQ ID NO: 298 GFTFSSYGISYDGSNK AKGPRYSSSWYISL YYYYGMDV LCDR SEQ ID NO: 299 SEQ ID NO: 300SEQ ID NO: 301 QSLVYSDGNTY KVS MQATHWPLYT P5A-1B6 HCDR SEQ ID NO: 306SEQ ID NO: 307 SEQ ID NO: 308 GFTFSSYA ISYDGSNK ARDGQAITMVQGV IGPPFDYLCDR SEQ ID NO: 309 SEQ ID NO: 310 SEQ ID NO: 311 QDISNY DAS QQYDNLPYTP5A-1B8 HCDR SEQ ID NO: 316 SEQ ID NO: 317 SEQ ID NO: 318 GFTVSSNYIYPGGST ARETLAFDY LCDR SEQ ID NO: 319 SEQ ID NO: 320 SEQ ID NO: 321QGISSY AAS QQLNSYPPA P5A-1B9 HCDR SEQ ID NO: 326 SEQ ID NO: 327SEQ ID NO: 328 GGSISSYY ISYSGST ASNGQYYDILTGQP PDYWYFDL LCDRSEQ ID NO: 329 SEQ ID NO: 330 SEQ ID NO: 331 QSVLYSSNNKNY WAS QQYYSTPLTP5A-1D1 HCDR SEQ ID NO: 336 SEQ ID NO: 337 SEQ ID NO: 338 GLTVSSNYIYSGGST ARDLYYYGMDV LCDR SEQ ID NO: 339 SEQ ID NO: 340 SEQ ID NO: 341QGISSY AAS QQLNSYPT P5A-1D10 HCDR SEQ ID NO: 346 SEQ ID NO: 347SEQ ID NO: 348 QFTFSDYS ISQSGSTI ARGVSPSYVWGSY RSLYHFDY LCDRSEQ ID NO: 349 SEQ ID NO: 350 SEQ ID NO: 351 SSDVGGYNY DVS SSFTSSTTVVVP5A-2D11 HCDR SEQ ID NO: 356 SEQ ID NO: 357 SEQ ID NO: 358 GYSFTSYWIYPGDSDT ARRDSTYGGNTDY LCDR SEQ ID NO: 359 SEQ ID NO: 360 SEQ ID NO: 361SSNIGSNT SNN AAWDDSLNGVV P5A-2G9 HCDR SEQ ID NO: 366 SEQ ID NO: 367SEQ ID NO: 368 GFTFSSYG IWYDGSNK ARWFHTGGYFDY LCDR SEQ ID NO: 369SEQ ID NO: 370 SEQ ID NO: 371 SDINVSSYN YYSDSDK MIWPSNALYV P5A-2H3 HCDRSEQ ID NO: 376 SEQ ID NO: 377 SEQ ID NO: 378 GYSFTSYW IYPGDSDTARRDSTYGGNTDY LCDR SEQ ID NO: 379 SEQ ID NO: 380 SEQ ID NO: 381 SSNIGSNTSNN AAWDDSLNGVV P5A-3A1 HCDR SEQ ID NO: 386 SEQ ID NO: 387SEQ ID NO: 388 GFTVSSNY IYSGGST ARDYGDFYFDY LCDR SEQ ID NO: 389SEQ ID NO: 390 SEQ ID NO: 391 QSVSSSY GAS QQYGSSPRT P5A-3A6 HCDRSEQ ID NO: 396 SEQ ID NO: 397 SEQ ID NO: 398 GFTFDDYA ISWNSGTIAGGGTMVRGVIAG GGTHPVDDYYGM DV LCDR SEQ ID NO: 399 SEQ ID NO: 400SEQ ID NO: 401 SSDVGGYNY DVS SSYTSSSTVV P5A-3B4 HCDR SEQ ID NO: 406SEQ ID NO: 407 SEQ ID NO: 408 GYSFTSYW IYPGDSDT ARRDSTYGGNTDY LCDRSEQ ID NO: 409 SEQ ID NO: 410 SEQ ID NO: 411 SSNIGSNT SNN AAWDDSLNGVVP5A-3C12 HCDR SEQ ID NO: 416 SEQ ID NO: 417 SEQ ID NO: 418 GFSLSTSGVGIYWDDDK AHSLFLTVGYSSSW SPFDY LCDR SEQ ID NO: 419 SEQ ID NO: 420SEQ ID NO: 421 QSVLYSSNNKNY WAS QQYYSTPHT P22A-1D1 HCDR SEQ ID NO: 426SEQ ID NO: 427 SEQ ID NO: 428 GFTVSSNY IYSGGST ARDRDYYGMDV LCDRSEQ ID NO: 429 SEQ ID NO: 430 SEQ ID NO: 431 QGISSY AAS LHLNSYRT

Table 2 below shows the heavy chain and light chain variable regionamino acid sequences of antibodies P2A-1A8, P2A-1A9, P2B-2G11, P2A-1A10,P2A-1B3, P2B-2F6, P2B-2G4, P2C-1A3, P2C-1C8, P2C-1C10, P2C-1D5,P2C-1F11, P2B-1G5, P2B-1A1, P2C- 1D7, P2B-1A10, P2B-1D9, P2B-1E4,P2B-1G1, P4A-2D9, P5A-2G7, P5A-3C8, P5A-1D2, P5A-2F11, P5A-2E1, P5A-1C8,P1A-1C10, P4A-1H6, P4B-1F4, P5A-1B6, P5A-1B8, P5A- 1B9, P5A-1D1,P5A-1D10, P5A-2D11, P5A-2G9, P5A-2H3, P5A-3A1, P5A-3A6, P5A-3B4,P5A-3C12, and P22A-1D1, and the corresponding nucleic acid encodingsequence are shown in Table 3.

TABLE 2 Variable region amino acid sequences of 42 antibodies VH VLP2A-1A8 SEQ ID NO: 7 SEQ ID NO: 8 EVQLVESGGDLVQPGRSLRLSCAQSALTQPASVSGSPGQSITISCTG ASGFAFDDYAMHWVRQAPGKG TSSDVGSYNLVSWYQQHPGKVPLEWVSGSTWNSGTIAYADSVKG KLLIYDVNKRPSGISNRFSGSKS RFTISRDNAKKSLYLQMNSLRTEGNTASLTISGLQAEDEADYYCRS DTALYYCAKLGGYSDYDYPRPG YTDSNTYVFGTGTKVTVLDHYYGLDVWGQGTTVTVSS P2A-1A9 SEQ ID NO: 17 SEQ ID NO: 18EVQLVESGGGLVQPGRSLRLSCA QSVLTQPPSVSGAPGQRVTISCT ASGFTFDDYAMHWVRQVPGKGLGSSSNIGAGYDVHWYQQLPGTA EWVSGISWNGGIIGYADSVKGRF PKLLIYGNNNRPSGVPDRFSGSKTISRDNAKTSLYLQMNSLRAEDT SGTSASLAITGLQAEDEADYYCQ ALYYCAKVAGRGDYDYYYGMDSYDSSLSGSVFGGGTKLTVL VWGQGTTVTVSS P2A-1A10 SEQ ID NO: 27 SEQ ID NO: 28QVQLVQSGAEVKKPGASVKVSC DIVMTQTPLSLPVTPGEPASISCR KASGYTFTGYYMHWVRQAPGQSSQSLLDSDDGNTYLDWYLQKP GLEWMGRINPNSGGTNYAQKFQ GQSPQLLIYTLSYRASGVPDRFSGRVTMTRDTSISTAYMELSRLRS GSGSGTDFTLKISRVEAEDVGVY DDTAVYYCARVPYCSSTSCHRDYCMQRIEFPLTFGGGTKVEIK WYFDLWGRGTLVTVSS P2A-1B3 SEQ ID NO: 37SEQ ID NO: 38 EVQLVESGGGLVQPGGSLRLSCV EIVLTQSPGTLSLSPGERATLSCRASGFSFNRYSMNWLRQTPRKGL ASQSVSNDYLAWYQQKPGQAP EWLSYISASGNTIYYADSVRGRFRLLIYYASSRATGIPDRFSGSGSG TTSRDNAKNTLYLQMNSLRDDD TDFTLTISRLEPGDSAVYYCQQYTAVYFCARPAMVREGTYNWFDP GDSPPITFGQGTRLEIK WGQGTLVTVSS P2B-2F6SEQ ID NO: 47 SEQ ID NO: 48 QVQLQESGPGLVKPSETLSLTCTQSALTQPPSASGSPGQSVTISCTG VSGYSISSGYWGWIRQPPGKGL TSSDVGGYNYVSWYQQHPGKAEWIGSIYHSGSTYYNPSLKTRVTI PKLMIYEVSKRPSGVPDRFSGSK SVDTSKNQFSLKLSSVTAADTAVSGNTASLTVSGLQAEDEADYYC YYCARAVVGIVVVPAAGRRAFDI SSYAGSNNLVFGGGTKLTVLWGQGTMVTVSS P2B-2G4 SEQ ID NO: 57 SEQ ID NO: 58 QVQLVESGGGVVQPGRSLRLSCAQSALTQPRSVSGSPGQSVTISCT ASGFTFSSYGIVIHWVRQAPGKGL GTSSDVGGYNYVSWYQQHPGKEWVAVIWYDGSNKYYADSVKG APKLMIYDVSKRPSGVPDRFSGS RFTISRDNSKNTLYLQMNSLRAEKSGNTASLTISGLQAEDEADYYC DTAVYYCARGAAMVWLDYWG CSYAGSYTFVVFGGGTKLTVLQGTLVTVSS P2B-2G11 SEQ ID NO: 61 SEQ ID NO: 62 EVQLVESGGGLVQPGRSLRLSCAQSVLTQPPSVSGAPGQRVTISCT ASGFTFDDYAMHWVRQAPGKGL GSSSNIGAGYDVHWYQQLPGTAEWVSGISWNGGIIGYADSVKGRF PKLLIYGNNNRPSGVPDRFSGSK TISRDNAKTSLYLQMNSLKPEDTSGTSASLAITGLQAEDEADYYCQ ALYYCAKVAGRGDYDYYYGMD SYDSSLSGSVFGGGTKLTVLVWGQGTTVTVSS P2C-1A3 SEQ ID NO: 71 SEQ ID NO: 72 QVQLVESGGGLVKPGGSLRLSCADIQLTQSPSFLSASVGDRVTITCR ASGFTFSDYYMSWIRQAPGKGLE ASQGISSYLAWYQQKPGKAPKLWVSYISSSGSTIYYADSVKGRFTI LIYAASTLQSGVPSRFSGSGSGTE SRDNAKNSLYLQMNSLRAEDTAFTLTISSLQPEDFATYYCQQLNS VYYCARDFSHQQLVPSWGQGTL YPLTFGGGTKVEIK VTVSSP2C-1C8 SEQ ID NO: 81 SEQ ID NO: 82 QVQLVESGGGVVQPGRSLRLSCADVVMTQSPLSLPVTLGQPASISC ASGFTFRSYGMHWVRQAPGKGL RSSQSLVYSDGNTYLNWFQQRPEWVAVIWYDGSNKYYADSVKG GQSPRRLIYKVSIWDSGVPDRFS RFTISRDNSKNTLYLQMNSLRAEGSGSGTDFTLKISRVEAEDVGVY DTAVYYCARDIEIVVVNIDYWGQ YCMQGTHWPYTFGQGTKLEIKGTLVTVSS P2C-1C10 SEQ ID NO: 91 SEQ ID NO: 92 QVQLVQSGAEVKKPGSSVKVSCEIVLTQSPATLSLSPGERATLSCR KASGGTFSSYAIIWVRQAPGQGL ASQSVSSYLAWYQQKPGQAPRLEWMGGIIPIFGTANYAQKFQGRV LIYDASNRATGIPARFSGSGSGT TITADESTSTAYMELSSLRSEDTADFTLTISSLEPEDFAVYYCQQRS VYYCARVVTGYYFDYWGQGTL NWPSFGQGTKLEIK VTVSSP2C-1D5 SEQ ID NO: 101 SEQ ID NO: 102 EVQLVESGGGLVQPGGSLRLSCASYVLTQPPSVSVAPGKTARITCG ASGFTFSSFAMSWVRQAPGKGLE GNNIGSKSVHWYQQKPGQAPVLWVSAISGSGGSTYYADSVKGRFT VIYYDSDRPSGIPERFSGSNSGNT ISRDNSKNTLYLQMNSLRAEDTAATLTISRVEAGDEADYYCQVWD VYYCAKDPDGSGSWYFDYWGQ SSSDHHVFGTGTKVTVL GTLVTVSSP2C-1F11 SEQ ID NO: 111 SEQ ID NO: 112

EIVLTQSPGTLSLSPGERATLSCR

ASQSVSSSYLAWYQQKPGQAPR

LLIYGASSRATGIPDRFSGSGSGT

DFTLTISRLEPEDFAVYYCQQYG

SSPTFGQGTKLEIK

P2B-1G5 SEQ ID NO: 142 SEQ ID NO: 143 QVQLVQSGSELKKPGASVKVSCSYVLTQPPSVSVAPGKTARITCG KASGYTFTTYVMNWVRQAPGQ GNNIGSKSVHWYQQKPGQAPVLGLEWMGWINTNTGNPTYAQGFT VIYYDSDRPSGIPERFSGSNSGNT GRFVFSLDTSVSTASLQISSLKAEATLTISGVEAGDEADYYCQVWD DTAVYYCSCEITTLGGMDVWGQ SISDHRVFGGGTKLTVL GTTVTVSSP2B-1A1 SEQ ID NO: 152 SEQ ID NO: 153 QVQLQESGPGLVKPSETLSLTCTQSALTQPASVSGSPGQSITISC VSGGSISSYYWSWIRQPPGKGLE TGTSSDVGGYNYVSWYQQHPWIGYIYYSGSTNYNPSLKSRVTIS GKAPKFMIYDVSKRPSGVSNR VDTSKKQFSLKLSSVTAADTAVYFSGSKSGNTASLTISGLQAEDE YCARLERDWPLDAFDIWGQGTM ADYYCSSYTSNNTFAFGGGT VTVSSKLTVL P2C-1D7 SEQ ID NO: 162 SEQ ID NO: 163 EVQLVESGGGLIQPGGSLRLSCADVVMTQSPLSLPVTLGQPASISC ASGFTVSSNYMSWVRQAPGKGL RSSQSLVYSDGNTYLNWFQQRPEWVSVIYSGGSTYYADSVKGRFT GQSPRRLIYKVSNWDSGVPDRFS ISRDNSKNTLYLQMNSLRAEDTAGSGSGTDFTLKISRVEAEDVGVY VYYCARELYEVGATDYWGQGTL YCMQRYTLAGVFGPGTKVDIKVTVSS P2B-1A10 SEQ ID NO: 172 SEQ ID NO: 173 EVQLVESGGGLIQPGGSLRLSCADIQMTQSPSSLSASVGDRVTITC ASGFTVSSNYMSWVRQAPGKGL QASQDISNYFNWYQQKPGKAPKEWVSVIYSGGSTYYADSVKGRFT LLIYDASNLETGVPSRFSGSGSG ISRDNSKNTLYLQMNSLRAEDTATDFTFTISSLQPEDIATYYCQQYD VYYCAREGPKSITGTAFDIWGQG NLPMYTFGQGTKLEIKTIVTVSS P2B-1D9 SEQ ID NO: 182 SEQ ID NO: 183 QITLKESGPTLVKPTQTLTLTCTFQSVLTQPPSASGTPGQRVTISCS SGFSLSTSGVGVGWIRQPPGKAL GSSSNIGSNYVYWYQQLPGTAPEWLALIYWDDDKYYSPSLKSRLT KLLIYSNNQRPSGVPDRFSGSKS ITKDTSKNQVVLTMTNMDPVDTGTSASLAISGLRSEDEADYYCAA ATYYCAHTRILYYGSGSYYDYW WDDSLSGVVFGGGTKLTVLGQGTLVTVSS P2B-1E4 SEQ ID NO: 192 SEQ ID NO: 193QITLKESGPTLVKPTQTLTLTCTF QSALTQPASVSGSPGQSITISCTGSGFSLSTSGVGVGWIRQPPGKAL TSSDVGGYNYVSWYQQHPGKA EWLALIYWDDDKRYSPSLKSRLTPKLMIYDVSKRPSGVSNRFSGSK ITKDTSKNQVVLTMTNMDPVDT SGNTASLTISGLQAEDEADYYCSATYYCAHQIVATIIDYWGQGTLV SYTSSSVVFGGGTKLTVL TVSS P2B-1G1 SEQ ID NO: 202SEQ ID NO: 203 EVQLVESGGGLVQPGGSLRLSCA EIVLTQSPGTLSLSPGERATLSCRASGFTVSSNYMSWVRQAPGKGL ASQSVSSSYLAWYQQKPGQAPR EWVSVIYSGGSTYYADSVKGRFTLLIYGASSRATGIPDRFSGSGSGT ISRDNSKNTLYLQMNSLRAEDTA DFTLTISRLEPEDFAVYYCQQYGVYYCARDYGDYWFDPWGQGTL SSPRTFGQGTKLEIK VTVSS P4A-2D9 SEQ ID NO: 212SEQ ID NO: 213 QVQLVESGGGVVQPGRSLRLSCA DIQMTQSPSSLSASVGDRVTITCASGFTFSSYGIVIHWVRQSPGKGL RASQFISSYLNWYQQKPGKAPK EWVAVISDDGSNQYYADSVKGRLLIYATSILQTGVPSRFSGSGSGT FTISRDNSKNTLYLEINSLRVEDTDFTLTISSLQPEDFATYYCQQSY AVYYCAKRGGYCSTTSCLVRWV NTLTFGPGTKVDIKYFDYWGQGTLVTVSS P5A-2G7 SEQ ID NO: 222 SEQ ID NO: 223QVQLQESGPGLVKPSETLSLTCT QSALTQPASVSGSPGQSITISCTG VSGDSVSSGSYYWSWIRQPPGKGTSSDVGGYNYVSWYQQHPGKA LEWIGYIYYSGSTNYNPSLKSRVT PKLMIYDVSNRPSGVSNRFSGSKISVDTSKNQFSLKLSSVTAADTA SGNTASLTISGLQAEDEADYYCS VYYCARERCYYGSGRAPRCVWFSYTSSSTLVVFGGGTKLTVL DPWGQGTLVTVSS P5A-3C8 SEQ ID NO: 232 SEQ ID NO: 233

DIQLTQSPSSLSASVGDRVTITCR

ASQGISSYLAWYQQKPGKAPKL

LIYAASTLQSGVPSRFSGSGSGT

DFTLTISSLQPEDFATYYCQHLN

SYPPGYTFGQGTKLEIK

P5A-1D2 SEQ ID NO: 242 SEQ ID NO: 243

QSVLTQPPSVSGAPGQRVTISCT

GSSSNIGAGYDVHWYQQLPGTA

SPKLLIYGNSNRPSGVPDRFSGSK

SGTSASLAITGLQAEDETDYYCQ

SCDSSLSVVVFGGGTKLTVL

P5A-2F11 SEQ ID NO: 252 SEQ ID NO: 253 QVQLVQSGAEVKKPGASVKVSCDIVMTQSPDSLAVSLGERATINC KASGYTFTSYDINWVRQATGQG KSSQSVLYSSNNKNYLAWYQQLEWMGWMNPNSGNTGYAQKFQ KPGQPPKLLIYWASTRESGVPDR GRVTMTRNTSISTAYMELSSLRSFSGSGSGTDFTLTISSLQAEDVA EDTAVYYCARYIVVVPAAKGFD VYYCQQYYSTPLTFGGGTKVEIPWGQGTLVTVSS K P5A-2E1 SEQ ID NO: 262 SEQ ID NO: 263EVQLVQSGAEVKKPGESLKISCK SYVLTQPPSVSVAPGKTARITCG GSGYSFTSYWIGWVRQMPGKGLGNNIGSKSVHWYQQKPGQAPVL EWMGIIYPGDSDTRYSPSFQGQV VIYYDSDRPSGIPERFSGSNSGNTTISADKSISTAYLQWSSLKASDTA ATLTISRVEAGDEADYYCQVWD MYYCAQTSVTRNWFDPWGQGTSSSDHVVFGGGTKLTVL LVTVSS P5A-1C8 SEQ ID NO: 272 SEQ ID NO: 273QVQLVQSGAEVKKPGASVKVSC DIQMTQSPSSLSASVGDRVTITC KASGYTFTSYYMHWVRQAPGQGQASQDISNYLNWYQQKPGKAPK LEWMGIINPSGGSTSYAQKFQGR LLIYDASNLETGVPSRFSGSGSGVTMTRDTSTSTVYMELSSLRSED TDFTFTISSLQPEDIATYYCQQYD TAVYYCARSARDYYDSSGYYYRNLPSITFGQGTRLEIK AEYFQHWGQGTLVTVSS P1A-1C10 SEQ ID NO: 282SEQ ID NO: 283 QVQLVQSGAEVKNPGSSVKVSC DIQMTQSPSTLSASVGDRVTITCKAGGGTSSFYDINWVRQAPGQG RASQSSRAWLAWYQQKPGKAP LEWIGKIIPRLDIADYAQKSQGRVKLLISKASSLESGVPSRFSGSGYG TITADKSTSTVYLELSSLKSDDTATEFTLTISSLQPDDSATYYCHQY VYFCARGRPGSEWAYGPFDLWG NSSPFTFGPGTKVQIKQGTLVTVSS P4A-1H6 SEQ ID NO: 292 SEQ ID NO: 293 QVQLVESGGGVVQPGRSLRLSCADIQMTQSPSSLSASVGDRVTITC ASGFTFSSYGIVIHWVRQSPGKGL RASQSISSYLHWYQQKPGKAPNEWVAVISDDGSNQYYADSVKGR LLIYAASSLQSGVPSRFSGSGSGT FTISRDNSKNTLYLQMNSLRVEDDFTLTISSLQPEDFATYYCQQSY TAVYYCAKRGGYCSTTSCLLRW NTPTFGPGTKVDIKVYFDFWGQGTLATVS S P4B-1F4 SEQ ID NO: 302 SEQ ID NO: 303QVQLVESGGGVVQPGRSLRLSCA DVVMTQSPLSLPVTLGQPASISC ASGFTFSSYGIVIHWVRQAPGKGLRSSQSLVYSDGNTYLNWFQQRP EWVAVISYDGSNKYYADSVKGR GQSPRRLIYKVSNRDSGVPDRFSFTISRDNSKNTLYLQINSLRAEDT GSGSGTDFTLKISRVEAEDVGVY AVYYCAKGPRYSSSWYISLYYYYCMQATHWPLYTFGQGTKLEIK YGMDVWGQGTTVTVSS P5A-1B6 SEQ ID NO: 312SEQ ID NO: 313 QVQLVESGGGVVQPGRSLRLSCA DIQMTQSPSSLSASVGDRVTITCASGFTFSSYAMIHWVRQAPGKGL QASQDISNYLNWYQQKPGKAPK EWVAVISYDGSNKYYADSVKGRLLIYDASNLETGVPSRFSGSGSG FTISRDNSKNTLYLQMNSLRAED TDFTFTISSLQPEDIATYYCQQYDTAVYYCARDGQAITMVQGVIGPP NLPYTFGQGTKLEIK FDYWGQGTLVTVSS P5A-1B8SEQ ID NO: 322 SEQ ID NO: 323 EVQLVESGGGLIQPGGSLRLSCADIQLTQSPSFLSASVGDRVTITCR ASGFTVSSNYMSWVRQAPGKGL ASQGISSYLAWYQQKPGKAPKLEWVSVIYPGGSTFYADSVKGRFT LIYAASTLQSGVPSRFSGSGSGTE ISRDNSKNTLYLQMNSLRAEDTAFTLTISSLQPEDFATYYCQQLNS VYYCARETLAFDYWGQGTLVTV YPPAFGGGTKVEIK SS P5A-1B9SEQ ID NO: 332 SEQ ID NO: 333 QVQLQESGPGLVKPSETLSLTCTDIVMTQSPDSLAVSLGERATINC VSGGSISSYYWSWIRQPPGKGLE KSSQSVLYSSNNKNYLAWYQQWIGYISYSGSTNYNPSLKSRVTIS KPGQPPKLLIYWASTRESGVPDR LDTSKNQFSLKLSSVTAADTAVYFSGSGSGTDFTLTISSLQAEDVA YCASNGQYYDILTGQPPDYWYF VYYCQQYYSTPLTFGGGTKVEIDLWGRGTLVTVSS K P5A-1D1 SEQ ID NO: 342 SEQ ID NO: 343EVQLVESGGGLIQPGGSLRLSCA DIQLTQSPSFLSASVGDRVTITCR ASGLTVSSNYMSWVRQAPGKGLASQGISSYLAWYQQKPGKAPKL EWVSVIYSGGSTYYADSVKGRFT LIYAASTLQSGVPSRFSGSGSGTISRDNSKNTLYLQMNSLRAEDTA DFTLTISSLQPEDFATYYCQQLN VYYCARDLYYYGMDVWGQGTTSYPTFGQGTRLEIK VTVST P5A-1D10 SEQ ID NO: 352 SEQ ID NO: 353QVQLVESGGGLVKPGGSLRLSCA QSALTQPASVSGSPGQSITISCTG ASQFTFSDYSMTWIRQAPGKGLETSSDVGGYNYVSWYQQHPGKA WVSYISQSGSTIYYADSVKGRFTI PKLMIYDVSNRPSGVSNRFSASKSRDNAKNSLYLQMNSLRAEDTA SGNTASLTISGLQAEDEADYYCS VYYCARGVSPSYVWGSYRSLYHSFTSSTTVVVFGGGTKLTVL FDYWGQGTLVTVSS P5A-2D11 SEQ ID NO: 362SEQ ID NO: 363 EVQLVQSGAEVKKPGESLKISCK QSVLTQPPSASGTPGQRVTISCSGSGYSFTSWIGWVRQMPGKGL GSSSNIGSNTVNWYQQLPGTAP EWMGIIYPGDSDTRYSPSFQGQVKLLIYSNNQRPSGVPDRFSGSKS TISADKSISTAYLQWSSLKASDTA GTSASLAISGLQSEDEADYYCAAMYYCARRDSTYGGNTDWGQG WDDSLNGVVFGGGTKLTVL TLVTVSS P5A-2G9 SEQ ID NO: 372SEQ ID NO: 373 QVQLVESGGGVVQPGRSLRLSCA QPVLTQPPSSSASPGESARLTCTLASGFTFSSYGMEIWVRQAPGKGL PSDINVSSYNIYWYQQKPGSPPR EWVAVIWYDGSNKYYADSVKGYLLYYYSDSDKGQGSGVPSRFS RFTISRDNSKNTLYLQMNSLRAE GSKDASANTGILLISGLQSEDEADTAVYYCARWFHTGGYFDYWG DYYCMIWPSNALYVFGTGTKVT QGTLVTVSS VL P5A-2H3SEQ ID NO: 382 SEQ ID NO: 383 EVQLVQSGAEVKKPGESLKISCKQSVLTQPPSASGTPGQRVTISCS GSGYSFTSWIGWVRQMPGKGL GSSSNIGSNTVNWYQQLPGTAPEWMGIIYPGDSDTRYSPSFQGQV KLLIYSNNQRPSGVPDRFSGSKS TISAEKSISTAYLQWSSLKASDTAGTSASLAISGLQSEDEADYYCAA MYYCARRDSTYGGNTDWGQG WDDSLNGVVFGGGTKLTVL TLVTVSSP5A-3A1 SEQ ID NO: 392 SEQ ID NO: 393 EVQLVESGGGLIQPGGSLRLSCAEIVLTQSPGTLSLSPGERATLSCR ASGFTVSSNYMSWVRQAPGKGL ASQSVSSSYLAWYQQKPGQAPREWVSVIYSGGSTYYADSVKGRFT LLIYGASSRATGIPDRFSGSGSGT ISRDNSKNTLYLQMNSLRAEDTADFTLTISRLEPEDFAVYYCQQYG VYYCARDYGDFYFDYWGQGTL SSPRTFGQGTKLEIK VTVSSP5A-3A6 SEQ ID NO: 402 SEQ ID NO: 403 EVQLVESGGGLVQPGRSLRLSCAQSALTQPASVSGSPGQSITISCTG ASGFTFDDYAMHWVRQAPGKGL TSSDVGGYNYVSWYQQHPGKAEWVSGISWNSGTIGYADSVKGRF PKLMIYDVSNRPSGVSNRFSGSK IISRDNAKNSLYLQMNSLRAEDTSGNTASLTISGLQAEDEADYYCS ALYYCAGGGTMVRGVIAGGGTH SYTSSSTVVFGGGTKLTVLPVDDYYGMDVWGQGTTVTVSS P5A-3B4 SEQ ID NO: 412 SEQ ID NO: 413EVQLVQSGAEVKEPGESLKISCK QSVLTQPPSASGTPGQRVTISCS GSGYSFTSYWIGWVRQMPGKGLGSSSNIGSNTVNWYQQLPGTAP EWMGIIYPGDSDTRYSPSFQGQV KLLIYSNNQRPSGVPDRFSGSKSTISADKSISTAYLQWSSLKASDTA GTSASLAISGLQSEDEADYYCAA MYYCARRDSTYGGNTDYWGQGWDDSLNGVVFGGGTKLTVL TLVTVSS P5A-3C12 SEQ ID NO: 422 SEQ ID NO: 423QITLKESGPTLVKPTQTLTLTCTF DIVMTQSPDSLAVSLGERATINC SGFSLSTSGVGVGWIRQPPGKALKSSQSVLYSSNNKNYLAWYQQ EWLALIYWDDDKRYSPSLKSRLT KPGQPPKLLIYWASTRESGVPDRITKDTSKNQVVLTMTNMDPVDT FSGSGSGTDFTLTISSLQAEDVA ATYYCAHSLFLTVGYSSSWSPFDVYYCQQYYSTPHTFGQGTKLEI YWGQGTLVTVSS K P22A-1D1 SEQ ID NO: 432SEQ ID NO: 433

DIQLTQSPSFLSASVGDRVTITCR

ASQGISSYLAWYQQKPGKAPKL

LIYAASTLQSGVPSRFSGSGSGTE

FTLTISSLQPEDFATYYCLHLNSY

RTFGLGTKVEIK

TABLE 3 Variable region nucleotide sequences of 42 antibodiesVHnu (nucleic acid) VLnu (nucleic acid) P2A-1A8 SEQ ID NO: 9SEQ ID NO: 10 GAAGTGCAGCTGGTGGAGTCTG CAGTCTGCCCTGACTCAGCCTGGGGGAGACTTGGTACAGCCTGG CCTCCGTGTCTGGGTCTCCTGG CAGGTCCCTGAGACTCTCCTGCACAGTCGATCACCATCTCCTGC GCAGCCTCTGGATTCGCCTTTG ACTGGAACCAGCAGTGATGTTATGATTATGCCATGCACTGGGT GGGAGTTATAACCTTGTCTCCT CCGGCAAGCTCCAGGGAAGGGGGTACCAACAGCACCCAGGCA CCTGGAGTGGGTCTCAGGTAGT AAGTCCCCAAACTCTTGATTTAACTTGGAATAGTGGGACCATAG TGATGTCAATAAGCGGCCCTCA CCTATGCGGACTCTGTGAAGGGGGGATTTCCAATCGCTTCTCTG CCGATTCACCATCTCCAGAGAC GCTCCAAGTCTGGCAACACGGAACGCCAAGAAGTCCCTGTATC CCTCCCTGACCATCTCTGGGCT TGCAAATGAACAGTCTGAGAACCCAGGCTGAGGACGAGGCTGA TGAGGACACGGCCTTATATTAC TTATTACTGCAGATCATATACATGTGCAAAGTTGGGGGGCTACA GACAGCAACACTTATGTCTTCG GTGACTACGATTACCCGAGGCCGAACTGGGACCAAGGTCACCG GGGAGACCACTATTACGGTTTG TCCTAGACGTCTGGGGCCAAGGGACCA CGGTCACCGTCTCCTCA P2A-1A9 SEQ ID NO: 19SEQ ID NO: 20 GAAGTGCAGCTGGTGGAGTCTG CAGTCTGTGCTGACGCAGCCGCGGGGAGGCTTGGTACAGCCTGG CCTCAGTGTCTGGGGCCCCAGG CAGGTCCCTGAGACTCTCCTGTGCAGAGGGTCACCATCTCCTGC GCAGCCTCTGGATTCACCTTTG ACTGGGAGCAGCTCCAACATCATGATTATGCCATGCACTGGGT GGGGCAGGTTATGATGTACAC CCGGCAAGTTCCAGGGAAGGGCTGGTACCAGCAACTTCCAGGA CTGGAGTGGGTCTCAGGTATTA ACAGCCCCCAAACTCCTCATCTGTTGGAATGGTGGTATCATAGG ATGGTAACAACAATCGCCCCTC CTACGCGGACTCTGTGAAGGGCAGGGGTCCCTGACCGATTCTCT CGATTCACCATCTCCAGAGACA GGCTCCAAGTCTGGCACCTCAGACGCCAAGACTTCCCTGTATCT CCTCCCTGGCCATCACTGGGCT GCAAATGAACAGTCTGAGAGCTCCAGGCTGAGGATGAGGCTGA GAGGACACGGCCTTGTATTACT TTATTACTGCCAGTCCTATGACGTGCAAAAGTCGCGGGAAGGG AGCAGCCTGAGTGGTTCGGTAT GGGATTACGACTATTACTATGGTCGGCGGAGGGACCAAGCTGA TATGGACGTCTGGGGCCAAGGG CCGTCCTAACCACGGTCACCGTCTCCTCA P2A-1A10 SEQ ID NO: 29 SEQ ID NO: 30CAGGTGCAGCTGGTGCAGTCTG GATATTGTGATGACCCAGACTC GGGCTGAGGTGAAGAAGCCTGCACTCTCCCTGCCCGTCACCCC GGGCCTCAGTGAAGGTCTCCTG TGGAGAGCCGGCCTCCATCTCCCAAGGCTTCTGGATACACCTTC TGCAGGTCTAGTCAGAGCCTCT ACCGGCTACTATATGCACTGGGTGGATAGTGATGATGGAAACA TGCGACAGGCCCCTGGACAAGG CCTATTTGGACTGGTACCTGCAGCTTGAGTGGATGGGACGGATC GAAGCCAGGGCAGTCTCCACA AACCCTAACAGTGGTGGCACAAGCTCCTGATCTATACGCTTTCC ACTATGCACAGAAGTTTCAGGG TATCGGGCCTCTGGAGTCCCAGCAGGGTCACCATGACCAGGGAC ACAGGTTCAGTGGCAGTGGGT ACGTCCATCAGCACAGCCTACACAGGCACTGATTTCACACTGAA TGGAGCTGAGCAGGCTGAGATC AATCAGCAGGGTGGAGGCTGATGACGACACGGCCGTGTATTAC GGATGTTGGAGTTTATTACTGC TGTGCGAGAGTCCCCTATTGTAATGCAACGTATAGAGTTTCCGC GTAGTACCAGCTGCCATCGGGA TCACTTTCGGCGGAGGGACCACTGGTACTTCGATCTCTGGGGC AGGTGGAGATCAAA CGTGGCACCCTGGTCACTGTCT CCTCAP2A-1B3 SEQ ID NO: 39 SEQ ID NO: 40 GAGGTGCAGCTGGTGGAGTCTGGAAATTGTGTTGACGCAGTCTC GGGGAGGCTTGGTACAGCCTGG CAGGCACCCTGTCTTTGTCTCCGGGGTCCCTCAGACTCTCCTGT AGGGGAAAGAGCCACCCTCTC GTCGCCTCTGGATTCTCCTTCAACTGCAGGGCCAGTCAGAGTGT TCGATATAGTATGAATTGGCTC TAGCAACGACTACTTAGCCTGGCGCCAGACTCCACGGAAGGGGC TACCAGCAGAAACCTGGCCAG TGGAGTGGCTTTCATACATCAGGCTCCCAGGCTCCTCATCTACT TGCCAGTGGAAACACCATATAC ATGCATCCAGCAGGGCCACTGTACGCTGACTCTGTGAGGGGCC GCATCCCAGACAGGTTCAGTG GATTCACCACCTCCAGAGACAAGCAGTGGGTCTGGGACAGACT TGCCAAGAACACACTGTATCTG TCACTCTCACCATCAGCAGACTCAAATGAACAGCCTGCGAGACG GGAGCCTGGAGATTCTGCAGT ACGACACGGCTGTCTATTTCTGGTATTACTGTCAGCAGTATGGT TGCGCGACCCGCTATGGTTCGG GACTCACCTCCGATCACCTTCGGAGGGGACCTACAACTGGTTCG GCCAAGGGACACGACTGGAGA ACCCCTGGGGCCAGGGAACCCTTTAAA GGTCACCGTCTCCTCA P2B-2F6 SEQ ID NO: 49 SEQ ID NO: 50CAGGTGCAGCTGCAGGAGTCGG CAGTCTGCCCTGACTCAGCCTC GCCCAGGACTGGTGAAGCCTTCCCTCCGCGTCCGGGTCTCCTGG GGAGACCCTGTCCCTCACCTGC ACAGTCAGTCACCATCTCCTGCACTGTCTCTGGTTACTCCATCAG ACTGGAACCAGCAGTGACGTT CAGTGGTTACTACTGGGGCTGGGGTGGTTATAACTATGTCTCCT ATCCGGCAGCCCCCAGGGAAGG GGTACCAACAGCACCCAGGCAGGCTGGAGTGGATTGGGAGTAT AAGCCCCCAAACTCATGATTTA CTATCATAGTGGGAGCACCTACTGAGGTCAGTAAGCGGCCCTC TACAACCCGTCCCTCAAGACTC AGGGGTCCCTGATCGCTTCTCTGAGTCACCATATCAGTAGACAC GGCTCCAAGTCTGGCAACACG GTCCAAGAACCAGTTCTCCCTGGCCTCCCTGACCGTCTCTGGGC AAGCTGAGCTCTGTGACCGCCG TCCAGGCTGAGGATGAGGCTGCAGACACGGCCGTCTATTACTG ATTATTACTGCAGCTCATATGC TGCGAGAGCGGTGGTAGGGATTAGGCAGCAACAATTTGGTGTTC GTAGTAGTACCAGCTGCCGGTC GGCGGAGGGACCAAGCTGACCGTCGGGCTTTTGATATCTGGGG GTCCTA CCAAGGGACAATGGTCACCGTC TCCTCA P2B-2G4SEQ ID NO: 59 SEQ ID NO: 60 CAGGTGCAGCTGGTGGAGTCTGCAGTCTGCCCTGACTCAGCCTC GGGGAGGCGTGGTCCAGCCTGG GCTCAGTGTCCGGGTCTCCTGGGAGGTCCCTGAGACTCTCCTGT ACAGTCAGTCACCATCTCCTGC GCAGCGTCTGGATTCACCTTCAACTGGAACCAGCAGTGATGTT GTAGCTATGGCATGCACTGGGT GGTGGTTATAACTATGTCTCCTCCGCCAGGCTCCAGGCAAGGGG GGTACCAACAGCACCCAGGCA CTGGAGTGGGTGGCAGTTATATAAGCCCCCAAACTCATGATTTA GGTATGATGGAAGTAATAAATA TGATGTCAGTAAGCGGCCCTCACTATGCAGACTCCGTGAAGGGC GGGGTCCCTGATCGCTTCTCTG CGATTCACCATCTCCAGAGACAGCTCCAAGTCTGGCAACACGG ATTCCAAGAACACGCTGTATCT CCTCCCTGACCATCTCTGGGCTGCAAATGAACAGCCTGAGAGCC CCAGGCTGAGGATGAGGCTGA GAGGACACGGCTGTGTATTACTTTATTACTGCTGCTCATATGCA GTGCGAGAGGGGCAGCTATGGT GGCAGCTACACTTTCGTGGTATTTGGCTTGACTACTGGGGCCAG TCGGCGGAGGGACCAAGCTGA GGAACCCTGGTCACCGTCTCCTCCGTCCTA CA P2B-2G11 SEQ ID NO: 63 SEQ ID NO: 64 GAAGTGCAGCTGGTGGAGTCTGCAGTCTGTGCTGACGCAGCCGC GGGGAGGCTTGGTACAGCCTGG CCTCAGTGTCTGGGGCCCCAGGCAGGTCCCTGAGACTCTCCTGT GCAGAGGGTCACCATCTCCTGC GCAGCCTCTGGATTCACCTTTGACTGGGAGCAGCTCCAACATC ATGATTATGCCATGCACTGGGT GGGGCAGGTTATGATGTACACCCGGCAAGCTCCAGGGAAGGG TGGTACCAGCAACTTCCAGGA CCTGGAGTGGGTCTCAGGTATTACAGCCCCCAAACTCCTCATCT AGTTGGAATGGTGGTATCATAG ATGGGAACAACAATCGGCCCTGCTATGCGGACTCTGTGAAGGG CAGGGGTCCCTGACCGATTCTC CCGATTCACCATCTCCAGAGACTGGCTCCAAGTCTGGCACCTCA AACGCCAAGACTTCCCTGTATC GCCTCCCTGGCCATCACTGGGCTGCAAATGAACAGTCTGAAACC TCCAGGCTGAGGATGAGGCTG TGAGGACACGGCCTTGTATTACATTATTACTGCCAGTCCTATGA TGTGCAAAAGTCGCGGGAAGG CAGCAGCCTGAGTGGTTCGGTGGGGATTACGACTACTACTACG ATTCGGCGGAGGGACCAAGCT GTATGGACGTCTGGGGCCAAGGGACCGTCCTA GACCACGGTCACCGTCTCCTCA P2C-1A3 SEQ ID NO: 73 SEQ ID NO: 74CAGGTGCAGCTGGTGGAGTCTG GACATCCAGTTGACCCAGTCTC GGGGAGGCTTGGTCAAGCCTGGCATCCTTCCTGTCTGCATCTGT AGGGTCCCTGAGACTCTCCTGT AGGAGACAGAGTCACCATCACGCAGCCTCTGGATTCACCTTCA TTGCCGGGCCAGTCAGGGCATT GTGACTACTACATGAGCTGGATAGCAGTTATTTAGCCTGGTATC CCGCCAGGCTCCAGGGAAGGG AGCAAAAACCAGGGAAAGCCCGCTGGAGTGGGTTTCATACATT CTAAGCTCCTGATCTATGCTGC AGTAGTAGTGGTAGTACCATATATCCACTTTGCAAAGTGGGGTC ACTACGCAGACTCTGTGAAGGG CCATCAAGGTTCAGCGGCAGTCCGATTCACCATCTCCAGGGAC GGATCTGGGACAGAATTCACT AACGCCAAGAACTCACTGTATCCTCACAATCAGCAGCCTGCAG TGCAAATGAACAGCCTGAGAGC CCTGAAGATTTTGCAACTTATTCGAGGACACGGCTGTGTATTAC ACTGTCAACAGCTTAATAGTTA TGTGCGAGAGATTTTTCTCATCCCCGCTCACTTTCGGCGGAGGG AGCAGCTGGTACCTTCCTGGGG ACCAAGGTGGAGATCAAACCAGGGAACCCTGGTCACCGTC TCCTCA P2C-1C8 SEQ ID NO: 83 SEQ ID NO: 84CAGGTGCAGCTGGTGGAGTCTG GATGTTGTGATGACTCAGTCTC GGGGAGGCGTGGTCCAGCCTGGCACTCTCCCTGCCCGTCACCCT GAGGTCCCTGAGACTCTCCTGT TGGACAGCCGGCCTCCATCTCCGCAGCGTCTGGATTCACCTTCA TGCAGGTCTAGTCAAAGCCTCG GGAGCTATGGCATGCACTGGGTTATACAGTGATGGAAACACCT CCGCCAGGCTCCAGGCAAGGGG ACTTGAATTGGTTTCAGCAGAGCTGGAGTGGGTGGCAGTTATCT GCCAGGCCAATCTCCAAGGCG GGTATGATGGAAGTAATAAATACCTAATTTATAAGGTTTCTATC CTATGCAGACTCCGTGAAGGGC TGGGACTCTGGGGTCCCAGACCGATTCACCATCTCCAGAGACA AGATTCAGCGGCAGTGGGTCA ATTCCAAGAACACGCTGTATCTGGCACTGATTTCACACTGAAA GCAAATGAACAGCCTGAGAGCC ATCAGCAGGGTGGAGGCTGAGGAGGACACGGCTGTGTATTACT GATGTTGGGGTTTATTACTGCA GTGCGAGAGATATAGAGATAGTTGCAAGGTACACACTGGCCGT AGTGGTAAATATTGACTACTGG ACACTTTTGGCCAGGGGACCAGGCCAGGGAACCCTGGTCACCG AGCTGGAGATCAAA TCTCCTCA P2C-1C10 SEQ ID NO: 93SEQ ID NO: 94 CAGGTGCAGCTGGTGCAGTCTG GAAATTGTGTTGACACAGTCTCGGGCTGAGGTGAAGAAGCCTG CAGCCACCCTGTCTTTGTCTCC GGTCCTCGGTGAAGGTCTCCTGAGGGGAAAGAGCCACCCTCTC CAAGGCTTCTGGAGGCACCTTC CTGCAGGGCCAGTCAGAGTGTAGCAGCTATGCTATCATCTGGG TAGCAGCTACTTAGCCTGGTAC TGCGACAGGCCCCTGGACAAGGCAACAGAAACCTGGCCAGGCT GCTTGAGTGGATGGGAGGGATC CCCAGGCTCCTCATCTATGATGATCCCTATCTTTGGTACAGCAA CATCCAACAGGGCCACTGGCA ACTACGCACAGAAGTTCCAGGGTCCCAGCCAGGTTCAGTGGCA CAGAGTCACGATTACCGCGGAC GTGGGTCTGGGACAGACTTCAGAATCCACGAGCACAGCCTACA CTCTCACCATCAGCAGCCTAGA TGGAGCTGAGCAGCCTGAGATCGCCTGAAGATTTTGCAGTTTAT TGAGGACACGGCCGTGTATTAC TACTGTCAGCAGCGTAGCAACTTGTGCGAGAGTGGTAACGGGGT GGCCTTCTTTTGGCCAGGGGAC ACTACTTTGACTACTGGGGCCACAAGCTGGAGATCAAA GGGAACCCTGGTCACCGTCTCC TCA P2C-1D5 SEQ ID NO: 103SEQ ID NO: 104 GAGGTGCAGCTGGTGGAGTCTG TCCTATGTGCTGACTCAGCCACGGGGAGGCTTGGTACAGCCTGG CCTCAGTGTCAGTGGCCCCAGG GGGGTCCCTGAGACTCTCCTGTAAAGACGGCCAGGATTACCTG GCAGCCTCTGGATTCACCTTTA TGGGGGAAACAACATTGGAAGGCAGCTTTGCCATGAGCTGGGT TAAAAGTGTGCACTGGTACCA CCGCCAGGCTCCAGGGAAGGGGCAGAAGCCAGGCCAGGCCCC GCTGGAGTGGGTCTCAGCTATT TGTGCTGGTCATCTATTATGATAGTGGTAGTGGTGGTAGCACAT AGCGACCGGCCCTCAGGGATC ACTACGCAGACTCCGTGAAGGGCCTGAGCGATTCTCTGGCTCCA CCGGTTCACCATCTCCAGAGAC ACTCTGGGAACACCGCCACCCTAATTCCAAGAACACGCTGTATT GACCATCAGCAGGGTCGAAGC TGCAAATGAACAGCCTGAGAGCCGGGGATGAGGCCGACTATTA CGAGGACACGGCCGTATATTAC CTGTCAGGTGTGGGATAGTAGTTGTGCGAAAGATCCGGATGGTT AGTGATCATCATGTCTTCGGAA CGGGGAGTTGGTACTTTGACTACTGGGACCAAGGTCACCGTCCT CTGGGGCCAGGGAACCCTGGTC A ACCGTCTCCTCA P2C-1F11SEQ ID NO: 113 SEQ ID NO: 114 GAGGTGCAGCTGGTGGAGTCTGGAAATTGTGTTGACGCAGTCTC GGGGAGGCTTGGTCCAGCCTGG CAGGCACCCTGTCTTTGTCTCCGGGGTCCCTGAGACTCTCCTGT AGGGGAAAGAGCCACCCTCTC GCAGCCTCTGGAATCACCGTCACTGCAGGGCCAGTCAGAGTGT GTAGCAACTACATGAACTGGGT TAGCAGCAGCTACTTAGCCTGGCCGCCAGGCTCCAGGGAAGGG TACCAGCAGAAACCTGGCCAG GCTGGAGTGGGTCTCACTTATTGCTCCCAGGCTCCTCATCTATG TATAGCGGTGGTAGCACATACT GTGCATCCAGCAGGGCCACTGACGCAGACTCCGTGAAGGGCAG GCATCCCAGACAGGTTCAGTG ATTCACCATCTCCAGAGACAATGCAGTGGGTCTGGGACAGACT TCCAAGAACACGTTGTATCTTC TCACTCTCACCATCAGCAGACTAAATGAACAGCCTGAGAGCCG GGAGCCTGAAGATTTTGCAGT AGGACACGGCTGTGTATCACTGGTATTACTGTCAGCAGTATGGT TGCGAGAGATCTGGTGGTATAC AGCTCACCCACTTTTGGCCAGGGGTATGGACGTCTGGGGCCAAG GGACCAAGCTGGAGATCAAA GGACCACGGTCACCGTCTCCTC AP2B-1G5 SEQ ID NO: 144 SEQ ID NO: 145 CAGGTGCAGCTGGTGCAATCTGTCCTATGTGCTGACTCAGCCAC GGTCTGAGTTGAAGAAGCCTGG CCTCAGTGTCAGTGGCCCCAGGGGCCTCAGTGAAGGTTTCCTGC AAAGACGGCCAGGATTACCTG AAGGCTTCTGGATACACCTTCATGGGGGAAACAACATTGGAAG CTACCTATGTTATGAATTGGGT TAAAAGTGTGCACTGGTACCAGCGACAGGCCCCTGGACAAGG GCAGAAGCCAGGCCAGGCCCC GCTTGAGTGGATGGGATGGATCTGTGCTGGTCATCTATTATGAT AACACCAACACTGGGAACCCAA AGCGACCGGCCCTCAGGGATCCGTATGCCCAGGGCTTCACAGG CCTGAGCGATTCTCTGGCTCCA ACGGTTTGTCTTCTCCTTGGACAACTCTGGGAACACGGCCACCC CCTCTGTCAGCACGGCATCTCT TGACCATCAGCGGGGTCGAAGGCAGATCAGCAGCCTAAAGGCT CCGGGGATGAGGCCGACTATT GAGGACACTGCCGTGTATTACTACTGTCAGGTGTGGGATAGTAT GTTCGTGTGAAATAACCACCTT TAGTGATCATCGGGTGTTCGGCGGGCGGTATGGACGTCTGGGGC GGAGGGACCAAGCTGACCGTC CAAGGGACCACGGTCACCGTCT CTACCTCA P2B-1A1 SEQ ID NO: 154 SEQ ID NO: 155 CAGGTGCAGCTGCAGGAGTCGGCAGTCTGCCCTGACTCAGCCTG GCCCAGGACTGGTGAAGCCTTC CCTCCGTGTCTGGGTCTCCTGGGGAGACCCTGTCCCTCACCTGC ACAGTCGATCACCATCTCCTGC ACTGTCTCTGGTGGCTCCATCAACTGGAACCAGCAGTGACGTT GTAGTTACTACTGGAGCTGGAT GGTGGTTATAACTATGTCTCCTCCGGCAGCCCCCAGGGAAGGG GGTACCAACAGCACCCAGGCA ACTGGAGTGGATTGGGTATATCAAGCCCCCAAATTCATGATTTA TATTACAGTGGGAGCACCAACT TGATGTCAGTAAGCGGCCCTCAACAACCCCTCCCTCAAGAGTCG GGGGTTTCTAATCGCTTCTCTG AGTCACCATATCAGTAGACACGGCTCCAAGTCTGGCAACACGG TCCAAGAAGCAGTTCTCCCTGA CCTCCCTGACCATCTCTGGGCTAGCTGAGCTCTGTGACCGCTGC CCAGGCTGAGGACGAGGCTGA GGACACGGCCGTGTATTACTGTTTATTACTGCAGCTCATATACA GCGAGGCTCGAACGAGACTGGC AGCAACAACACTTTCGCGTTCGCACTTGATGCTTTTGATATCTGG GCGGAGGGACCAAGCTGACCG GGCCAAGGGACAATGGTCACCGTCCTA TCTCCTCA P2C-1D7 SEQ ID NO: 164 SEQ ID NO: 165GAGGTGCAGCTGGTGGAGTCTG GATGTTGTGATGACTCAGTCTC GAGGAGGCTTGATCCAGCCTGGCACTCTCCCTGCCCGTCACCCT GGGGTCCCTGAGACTCTCCTGT TGGACAGCCGGCCTCCATCTCCGCAGCCTCTGGGTTCACCGTCA TGCAGGTCTAGTCAAAGCCTCG GTAGCAACTACATGAGCTGGGTTATACAGTGATGGAAACACCT CCGCCAGGCTCCAGGGAAGGG ACTTGAATTGGTTTCAGCAGAGGCTGGAGTGGGTCTCAGTTATT GCCAGGCCAATCTCCAAGGCG TATAGCGGTGGTAGCACATACTCCTAATTTATAAGGTTTCTAAC ACGCAGACTCCGTGAAGGGCCG TGGGACTCTGGGGTCCCAGACATTCACCATCTCCAGAGACAAT AGATTCAGCGGCAGTGGGTCA TCCAAGAACACGCTGTATCTTCGGCACTGATTTCACACTGAAA AAATGAACAGCCTGAGAGCCG ATCAGCAGGGTGGAGGCTGAGAGGACACGGCCGTGTATTACTG GATGTTGGGGTTTATTACTGCA TGCGAGAGAATTGTACGAAGTGTGCAACGGTACACACTGGCCG GGAGCTACGGACTACTGGGGCC GCGTTTTCGGCCCTGGGACCAAAGGGAACCCTGGTCACCGTCTC AGTGGATATCAAA CTCA P2B-1A10 SEQ ID NO: 174SEQ ID NO: 175 GAGGTGCAGCTGGTGGAGTCTG GACATCCAGATGACCCAGTCTCGAGGAGGCTTGATCCAGCCTGG CATCCTCCCTGTCTGCATCTGT GGGGTCCCTGAGACTCTCCTGTAGGAGACAGAGTCACCATCAC GCAGCCTCTGGGTTCACCGTCA TTGCCAGGCGAGTCAGGACATGTAGCAACTACATGAGCTGGGT TAGCAACTATTTTAATTGGTAT CCGCCAGGCTCCAGGGAAGGGCAGCAGAAACCAGGGAAAGCC GCTGGAGTGGGTCTCAGTTATT CCTAAGCTCCTGATCTACGATGTATAGCGGTGGTAGCACATACT CATCCAATTTGGAAACAGGGG ACGCAGACTCCGTGAAGGGCCGTCCCATCAAGGTTCAGTGGAA ATTCACCATCTCCAGAGACAAT GTGGATCTGGGACAGATTTTACTCCAAGAACACGCTGTATCTTC TTTCACCATCAGCAGCCTGCAG AAATGAACAGCCTGAGAGCCGCCTGAAGATATTGCAACATATT AGGACACGGCCGTTTATTACTG ACTGTCAACAGTATGATAATCTTGCGAGAGAGGGCCCAAAGTCT CCCCATGTACACTTTTGGCCAG ATTACAGGGACGGCTTTTGATAGGGACCAAGCTGGAGATCAAA TCTGGGGCCAAGGGACAATTGT CACCGTCTCCTCA P2B-1D9SEQ ID NO: 184 SEQ ID NO: 185 CAGATCACCTTGAAGGAGTCTGCAGTCTGTGCTGACTCAGCCAC GTCCTACGCTGGTGAAACCCAC CCTCAGCGTCTGGGACCCCCGGACAGACCCTCACGCTGACCTGC GCAGAGGGTCACCATCTCTTGT ACCTTCTCTGGGTTCTCACTCAGTCTGGAAGCAGCTCCAACATC CACTAGTGGAGTGGGTGTGGGC GGAAGTAATTATGTATACTGGTTGGATCCGTCAGCCCCCAGGAA ACCAGCAGCTCCCAGGAACGG AGGCCCTGGAGTGGCTTGCACTCCCCCAAACTCCTCATCTATAG CATTTATTGGGATGATGATAAA TAATAATCAGCGGCCCTCAGGTACTACAGCCCATCTCTGAAGA GGTCCCTGACCGATTCTCTGGC GCAGGCTCACCATCACCAAGGATCCAAGTCTGGCACCTCAGCCT CACCTCCAAAAACCAGGTGGTC CCCTGGCCATCAGTGGGCTCCGCTTACAATGACCAACATGGACC GTCCGAGGATGAGGCTGATTA CTGTGGACACAGCCACATATTATTACTGTGCAGCATGGGATGAC CTGTGCACACACTCGCATCTTA AGCCTGAGTGGTGTGGTATTCGTACTATGGTTCGGGGAGTTATT GCGGAGGGACCAAGCTGACCG ATGACTACTGGGGCCAGGGAACTCCTA CCTGGTCACCGTCTCCTCA P2B-1E4 SEQ ID NO: 194 SEQ ID NO: 195CAGATCACCTTGAAGGAGTCTG CAGTCTGCCCTGACTCAGCCTG GTCCTACGCTGGTGAAACCCACCCTCCGTGTCTGGGTCTCCTGG ACAGACCCTCACGCTGACCTGC ACAGTCGATCACCATCTCCTGCACCTTCTCTGGGTTCTCACTCAG ACTGGAACCAGCAGTGACGTT CACTAGTGGAGTGGGTGTGGGCGGTGGTTATAACTATGTCTCCT TGGATCCGTCAGCCCCCAGGAA GGTACCAACAGCACCCAGGCAAGGCCCTGGAGTGGCTTGCACT AAGCCCCCAAACTCATGATTTA CATTTATTGGGATGATGATAAGTGATGTCAGTAAGCGGCCCTCA CGCTACAGCCCATCTCTGAAGA GGGGTTTCTAATCGCTTCTCTGGCAGGCTCACCATCACCAAGGA GCTCCAAGTCTGGCAACACGG CACCTCCAAAAACCAGGTGGTCCCTCCCTGACCATCTCTGGGCT CTTACAATGACCAACATGGACC CCAGGCTGAGGACGAGGCTGACTGTGGACACAGCCACATATTA TTATTACTGCAGCTCATATACA CTGTGCACACCAAATAGTGGCTAGCAGCAGCGTGGTATTCGGC ACGATTATTGACTACTGGGGCC GGAGGGACCAAGCTGACCGTCAGGGAACCCTGGTCACCGTCTC CTA CTCA P2B-1G1 SEQ ID NO: 204 SEQ ID NO: 205GAGGTGCAGCTGGTGGAGTCTG GAAATTGTGTTGACGCAGTCTC GGGGAGGCTTGGTCCAGCCTGGCAGGCACCCTGTCTTTGTCTCC GGGGTCCCTGAGACTCTCCTGT AGGGGAAAGAGCCACCCTCTCGCAGCCTCTGGATTCACCGTCA CTGCAGGGCCAGTCAGAGTGT GTAGCAACTACATGAGCTGGGTTAGCAGCAGCTACTTAGCCTGG CCGCCAGGCTCCAGGGAAGGG TACCAGCAGAAACCTGGCCAGGCTGGAGTGGGTCTCAGTTATT GCTCCCAGGCTCCTCATCTATG TATAGCGGTGGTAGCACATACTGTGCATCCAGCAGGGCCACTG ACGCAGACTCCGTGAAGGGCAG GCATCCCAGACAGGTTCAGTGATTCACCATCTCCAGAGACAAT GCAGTGGGTCTGGGACAGACT TCCAAGAACACGCTGTATCTTCTCACTCTCACCATCAGCAGACT AAATGAACAGCCTGAGAGCCG GGAGCCTGAAGATTTTGCAGTAGGACACGGCTGTGTATTACTG GTATTACTGTCAGCAGTATGGT TGCGAGAGACTACGGTGACTACAGCTCACCGAGGACTTTTGGCC TGGTTCGACCCCTGGGGCCAGG AGGGGACCAAGCTGGAGATCAGAACCCTGGTCACCGTCTCCTC AA A P4A-2D9 SEQ ID NO: 214 SEQ ID NO: 215CAGGTGCAGCTGGTGGAGTCTG GACATCCAGATGACCCAGTCTC GGGGAGGCGTGGTCCAGCCTGGCATCCTCCCTGTCTGCATCTGT GAGGTCCCTGAGACTCTCCTGT AGGAGACAGAGTCACCATCACGCAGCCTCTGGATTCACCTTCA TTGCCGGGCAAGTCAGTTCATT GTAGCTATGGCATGCACTGGGTAGCAGCTACTTAAATTGGTATC CCGCCAGTCTCCAGGCAAGGGG AGCAGAAACCAGGGAAAGCCCCTGGAGTGGGTGGCAGTTATAT CTAAGCTCCTGATCTATGCTAC CAGATGATGGAAGTAATCAATAATCCATTTTGCAAACTGGGGTC CTATGCAGACTCCGTGAAGGGC CCATCAAGGTTCAGTGGCAGTCGATTCACCATCTCCAGAGACA GGATCTGGGACAGATTTCACTC ATTCCAAGAACACGCTGTATCTTCACCATCAGCAGTCTGCAACC GGAAATCAACAGCCTGAGAGTT TGAAGATTTTGCAACTTACTACGAGGACACGGCTGTGTATTACT TGTCAACAGAGTTACAATACCC GTGCGAAAAGGGGCGGATATTGTTACTTTCGGCCCTGGGACCAA TAGTACTACCAGCTGCCTCGTT AGTCGATATCAAAAGGTGGGTCTACTTTGACTACT GGGGCCAGGGAACCCTGGTCAC CGTCTCCTCA P5A-2G7SEQ ID NO: 224 SEQ ID NO: 225 CAGGTGCAGCTGCAGGAGTCCAGTCTGCCCTGACTCAGCCTG GGGCCCAGGACTGGTGAAGC CCTCCGTGTCTGGGTCTCCTGGCTTCGGAGACCCTGTCCCTCA ACAGTCGATCACCATCTCCTGC CCTGCACTGTCTCTGGTGACTACTGGAACCAGCAGTGACGTT CCGTCAGCAGTGGTAGTTAC GGTGGTTATAACTATGTCTCCTTACTGGAGCTGGATCCGGCA GGTACCAACAACACCCAGGCA GCCCCCAGGGAAGGGACTGGAAGCCCCCAAACTCATGATTTA AGTGGATTGGGTATATCTATT TGATGTCAGTAATCGGCCCTCAACAGTGGGAGCACCAACTAC GGGGTTTCTAATCGCTTCTCTG AACCCCTCCCTCAAGAGTCGGCTCCAAGTCTGGCAACACGG AGTCACCATATCAGTAGACA CCTCCCTGACCATCTCTGGGCTCGTCCAAGAACCAGTTCTCC CCAGGCTGAGGACGAGGCTGA CTGAAGCTGAGCTCTGTGACTTATTACTGCAGCTCATATACA CGCTGCGGACACGGCCGTGT AGCAGCAGCACTCTCGTGGTATATTACTGTGCGAGAGAGCGA TCGGCGGAGGGACCAAGCTGA TGTTACTATGGTTCAGGGAG CCGTCCTAAGCCCCCCGTTGTGTCTGGTT CGACCCCTGGGGCCAGGGAA CCCTGGTCACCGTCTCCTCA P5A-3C8SEQ ID NO: 234 SEQ ID NO: 235 GAGGTGCAGCTGGTGGAGTCTGGACATCCAGTTGACCCAGTCTC GAGGAGGCTTGATCCAGCCTGG CATCCTCCCTGTCTGCATCTGTGGGGTCCCTGAGACTCTCCTGT AGGAGACAGAGTCACCATCAC GCAGCCTCTGGGTTCACCGTCATTGCCGGGCCAGTCAGGGCATT GTAGCAACTACATGAGCTGGGT AGCAGTTATTTAGCCTGGTATCCCGCCAGGCTCCAGGGAAGGG AGCAAAAACCAGGGAAAGCCC GCTGGAATGGGTCTCATTTATTTCTAAGCTCCTGATCTATGCTGC ATAGCGGTGGTAGTACATACTA ATCCACTTTGCAAAGTGGGGTCCGCAGACTCCGTGAAGGGCCGA CCATCAAGGTTCAGCGGCAGT TTCACCATCTCCAGAGACAATTGGATCTGGGACAGATTTCACTC CCAAGAACACGCTGTATCTTCA TCACCATCAGCAGCCTGCAGCCAATGAACAGCCTGAGAGCCGA TGAAGATTTTGCAACTTATTAC GGACACGGCCGTGTATTACTGTTGTCAACACCTTAATAGTTACC GCGAGAGATCTACAGGAACAC CTCCGGGGTACACTTTTGGCCAGGTATGGACGTCTGGGGCCAAG GGGGACCAAGCTGGAGATCAA GGACCACGGTCACCGTCTCCTC A AP5A-1D2 SEQ ID NO: 244 SEQ ID NO: 245 GAGGTGCAGCTGGTGGAGTCTGCAGTCTGTGCTGACGCAGCCGC GAGGAGGCTTGATCCAGCCTGG CCTCAGTGTCTGGGGCCCCAGGGGGGTCCCTGAGACTCTCCTGT GCAGAGGGTCACCATCTCCTGC GCAGCCTCTGGGTTCATCGTCAACTGGGAGCAGCTCCAACATC GTAGCAACTACATGAGCTGGGT GGGGCAGGTTATGATGTACACCCGCCAGGCTCCAGGGAAGGG TGGTACCAGCAACTTCCAGGA GCTGGAGTGGGTCTCAATTATTACAGCCCCCAAACTCCTCATCT TATAGCGGTGGTAGCACATACT ATGGTAACAGCAATCGGCCCTACGCAGACTCCGTGAAGGGCCG CAGGGGTCCCTGACCGATTCTC ATTCACCATCTCCAGAGACAATTGGCTCCAAGTCTGGCACCTCA TCCAACAACACGCTGTATCTTC GCCTCCCTGGCCATCACTGGGCAAATGAACAGCCTGAGAGCCG TCCAGGCTGAAGATGAGACTG AGGACACGGCCGTATATTACTGATTATTACTGCCAGTCCTGTGA TGCGAGAGCCCTCCAGGTGGGA CAGCAGCCTGAGTGTTGTGGTAGCTACTTCGGACTACTTTGACT TTCGGCGGAGGGACCAAGCTG ACTGGGGCCAGGGAACCCTGGTACCGTCCTA CACCGTCTCCTCA P5A-2F11 SEQ ID NO: 254 SEQ ID NO: 255CAGGTGCAGCTGGTGCAGTCTG GACATCGTGATGACCCAGTCTC GGGCTGAGGTGAAGAAGCCTGCAGACTCCCTGGCTGTGTCTCT GGGCCTCAGTGAAGGTCTCCTG GGGCGAGAGGGCCACCATCAACAAGGCTTCTGGATACACCTTC CTGCAAGTCCAGCCAGAGTGTT ACCAGTTATGATATCAACTGGGTTATACAGCTCCAACAATAAG TGCGACAGGCCACTGGACAAGG AACTACTTAGCTTGGTACCAGCGCTTGAGTGGATGGGATGGATG AGAAACCAGGACAGCCTCCTA AACCCTAACAGTGGTAACACAGAGCTGCTCATTTACTGGGCATC GCTATGCACAGAAGTTCCAGGG TACCCGGGAATCCGGGGTCCCTCAGAGTCACCATGACCAGGAAC GACCGATTCAGTGGCAGCGGG ACCTCCATAAGCACAGCCTACATCTGGGACAGATTTCACTCTCA TGGAGCTGAGCAGCCTGAGATC CCATCAGCAGCCTGCAGGCTGTGAGGACACGGCCGTGTATTAC AAGATGTGGCAGTTTATTACTG TGTGCGAGATATATTGTAGTAGTCAGCAATATTATAGTACTCCT TACCAGCTGCAAAAGGGTTCGA CTCACTTTCGGCGGAGGGACCCCCCTGGGGCCAGGGAACCCTG AAGGTGGAGATCAAA GTCACCGTCTCCTCA P5A-2E1SEQ ID NO: 264 SEQ ID NO: 265 GAGGTGCAGCTGGTGCAGTCTGTCCTATGTGCTGACTCAGCCAC GAGCAGAGGTGAAAAAGCCCG CCTCAGTGTCAGTGGCCCCAGGGGGAGTCTCTGAAGATCTCCTG AAAGACGGCCAGGATTACCTG TAAGGGTTCTGGATACAGCTTTTGGGGGAAACAACATTGGAAG ACCAGCTACTGGATCGGCTGGG TAAAAGTGTGCACTGGTACCATGCGCCAGATGCCCGGGAAAGG GCAGAAGCCAGGCCAGGCCCC CCTGGAGTGGATGGGGATCATCTGTGCTGGTCATCTATTATGAT TATCCTGGTGACTCTGATACCA AGCGACCGGCCCTCAGGGATCGATACAGCCCGTCCTTCCAAGG CCTGAGCGATTCTCTGGCTCCA CCAGGTCACCATCTCAGCCGACACTCTGGGAACACGGCCACCC AAGTCCATCAGCACCGCCTACC TGACCATCAGCAGGGTCGAAGTGCAGTGGAGCAGCCTGAAGGC CCGGGGATGAGGCCGACTATT CTCGGACACCGCCATGTATTACACTGTCAGGTGTGGGATAGTA TGTGCCCAGACGTCAGTGACTC GTAGTGATCATGTGGTATTCGGGCAACTGGTTCGACCCCTGGGG CGGAGGGACCAAGCTGACCGT CCAGGGAACCCTGGTCACCGTC CCTATCCTCA P5A-1C8 SEQ ID NO: 274 SEQ ID NO: 275 CAGGTGCAGCTGGTGCAGTCTGGACATCCAGATGACCCAGTCTC GGGCTGAGGTGAAGAAGCCTG CATCCTCCCTGTCTGCATCTGTGGGCCTCAGTGAAGGTTTCCTG AGGAGACAGAGTCACCATCAC CAAGGCATCTGGATACACCTTCTTGCCAGGCGAGTCAGGACAT ACCAGCTACTATATGCACTGGG TAGCAACTATTTAAATTGGTATTGCGACAGGCCCCTGGACAAGG CAGCAGAAACCAGGGAAAGCC GCTTGAGTGGATGGGAATAATCCCTAAGCTCCTGATCTACGATG AACCCTAGTGGTGGTAGCACAA CATCCAATTTGGAAACAGGGGGCTACGCACAGAAGTTCCAGGG TCCCATCAAGGTTCAGTGGAA CAGAGTCACCATGACCAGGGACGTGGATCTGGGACAGATTTTAC ACGTCCACGAGCACAGTCTACA TTTCACCATCAGCAGCCTGCAGTGGAGCTGAGCAGCCTGAGATC CCTGAAGATATTGCAACATATT TGAGGACACGGCCGTGTATTACACTGTCAACAGTATGATAATCT TGTGCGAGGTCGGCCCGGGATT CCCCTCTATCACCTTCGGCCAAACTATGATAGTAGTGGTTATTA GGGACACGACTGGAGATTAAA CTACCGCGCTGAATACTTCCAGCACTGGGGCCAGGGCACCCTGG TCACCGTCTCCTCA P1A-1C10 SEQ ID NO: 284SEQ ID NO: 285 CAGGTGCAGCTGGTGCAGTCTG GACATCCAGATGACCCAGTCTCGGGCTGAGGTGAAGAACCCGG CTTCCACCCTGTCTGCATCTGT GGTCCTCGGTGAAGGTCTCCTGAGGAGACAGAGTCACCATCAC TAAGGCTGGTGGAGGCACCTCC TTGCCGGGCCAGTCAGAGTTCTAGTTTCTATGATATCAACTGGG AGGGCCTGGTTGGCCTGGTATC TGCGACAGGCCCCTGGACAAGGAGCAGAAACCAGGGAAAGCCC GCTTGAGTGGATAGGAAAAATC CTAAACTCCTGATCTCTAAGGCATCCCTAGGCTTGATATAGCAG GTCTAGTTTAGAAAGTGGGGTC ACTACGCACAGAAGTCCCAGGGCCATCAAGGTTCAGCGGCAGT CAGAGTCACGATTACCGCGGAC GGATATGGGACAGAATTCACTAAATCCACGAGTACAGTATACT CTCACCATCAGCAGCCTGCAGC TGGAATTGAGCAGCCTGAAGTCCTGATGATTCTGCAACTTATTA AGACGACACGGCCGTGTATTTC CTGCCACCAGTATAACAGTAGTGTGCGAGAGGTCGGCCGGGTT CCCATTCACTTTCGGCCCTGGG CGGAGTGGGCGTATGGCCCATTACCAAAGTGCAGATCAAA TGACCTCTGGGGCCAGGGAACC CTGGTCACCGTCTCCTCA P4A-1H6SEQ ID NO: 294 SEQ ID NO: 295 CAGGTGCAGCTGGTGGAGTCTGGACATCCAGATGACCCAGTCTC GGGGAGGCGTGGTCCAGCCTGG CATCCTCCCTGTCTGCATCTGTGAGGTCCCTGAGACTCTCCTGT AGGAGACAGAGTCACCATCAC GCAGCCTCTGGATTCACCTTCATTGCCGGGCAAGTCAGAGCAT GTAGCTATGGCATGCACTGGGT TAGCAGCTATTTACATTGGTATCCGCCAGTCTCCAGGCAAGGGG CAGCAAAAACCAGGGAAAGCC CTGGAGTGGGTGGCAGTTATATCCTAACCTCCTGATCTATGCTG CAGATGATGGAAGTAATCAATA CATCCAGTTTGCAAAGTGGGGTCTATGCAGACTCCGTGAAGGGC CCCATCAAGGTTCAGTGGCAGT CGATTCACCATCTCCAGAGACAGGATCTGGGACAGATTTCACTC ATTCCAAGAACACGCTGTATCT TCACCATCAGCAGTCTGCAACCGCAAATGAACAGCCTGAGAGTT TGAAGACTTTGCAACTTACTAC GAGGACACGGCTGTGTATTACTTGTCAACAGAGTTACAATACCC GTGCGAAAAGGGGCGGATATTG CTACTTTCGGCCCTGGGACCAATAGTACTACCAGCTGCCTCCTT AGTGGATATCAAA AGGTGGGTCTACTTTGACTTCTGGGGCCAGGGAACCCTGGCCAC CGTCTCCTCA P4B-1F4 SEQ ID NO: 304 SEQ ID NO: 305CAGGTGCAGCTGGTGGAGTCTG GATGTTGTGATGACTCAGTCTC GGGGAGGCGTGGTCCAGCCTGGCACTCTCCCTGCCCGTCACCCT GAGGTCCCTGAGACTCTCCTGT TGGACAGCCGGCCTCCATCTCCGCAGCCTCTGGATTCACCTTCA TGCAGGTCTAGTCAAAGCCTCG GTAGCTATGGCATGCACTGGGTTATACAGTGATGGAAACACCT CCGCCAGGCTCCAGGCAAGGGG ACTTGAATTGGTTTCAGCAGAGCTGGAGTGGGTGGCAGTTATAT GCCAGGCCAATCTCCAAGGCG CATATGATGGAAGTAATAAATACCTAATTTATAAGGTTTCTAAC CTATGCAGACTCCGTGAAGGGC CGGGACTCTGGGGTCCCAGACCGATTCACCATCTCCAGAGACA AGATTCAGCGGCAGTGGGTCA ATTCCAAGAACACGCTGTATCTGGCACTGATTTCACACTGAAA GCAAATCAACAGCCTGAGAGCT ATCAGCAGGGTGGAGGCTGAGGAGGACACGGCTGTGTATTACT GATGTTGGGGTTTATTACTGCA GTGCGAAAGGGCCTCGGTATAGTGCAAGCTACACACTGGCCCCT CAGCAGCTGGTACATAAGCCTT GTACACTTTTGGCCAGGGGACCTACTACTACTACGGTATGGACG AAGCTGGAGATCAAA TCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA P5A-1B6 SEQ ID NO: 314 SEQ ID NO: 315CAGGTGCAGCTGGTGGAGTCTG GACATCCAGATGACCCAGTCTC GGGGAGGCGTGGTCCAGCCTGGCATCCTCCCTGTCTGCATCTGT GAGGTCCCTGAGACTCTCCTGT AGGAGACAGAGTCACCATCACGCAGCCTCTGGATTCACCTTCA TTGCCAGGCGAGTCAGGACAT GTAGCTATGCTATGCACTGGGTTAGCAACTATTTAAATTGGTAT CCGCCAGGCTCCAGGCAAGGGG CAGCAGAAACCAGGGAAAGCCCTGGAGTGGGTGGCAGTTATAT CCTAAGCTCCTGATCTACGATG CATATGATGGAAGTAATAAATACATCCAATTTGGAAACAGGGG CTACGCAGACTCCGTGAAGGGC TCCCATCAAGGTTCAGTGGAACGATTCACCATCTCCAGAGACA GTGGATCTGGGACAGATTTTAC ATTCCAAGAACACGCTGTATCTTTTCACCATCAGCAGCCTGCAG GCAAATGAACAGCCTGAGAGCT CCTGAAGATATTGCAACATATTGAGGACACGGCTGTGTATTACT ACTGTCAACAGTATGATAATCT GTGCGAGAGATGGACAGGCTATCCCGTACACTTTTGGCCAGGGG TACTATGGTTCAGGGAGTTATC ACCAAGCTGGAGATCAAAGGCCCACCCTTTGACTACTGGG GCCAGGGAACCCTGGTCACCGT CTCCTCA P5A-1B8SEQ ID NO: 324 SEQ ID NO: 325 GAGGTGCAGCTGGTGGAGTCTGGACATCCAGTTGACCCAGTCTC GAGGAGGCTTGATCCAGCCTGG CATCCTTCCTGTCTGCATCTGTGGGGTCCCTGAGACTCTCCTGT AGGAGACAGAGTCACCATCAC GCAGCCTCTGGGTTCACCGTCATTGCCGGGCCAGTCAGGGCATT GTAGCAACTACATGAGCTGGGT AGCAGTTATTTAGCCTGGTATCCCGCCAGGCTCCAGGGAAGGG AGCAAAAACCAGGGAAAGCCC GCTGGAGTGGGTCTCAGTTATTCTAAGCTCCTGATCTATGCTGC TATCCCGGTGGTAGCACATTCT ATCCACTTTGCAAAGTGGGGTCACGCAGACTCCGTGAAGGGCCG CCATCAAGGTTCAGCGGCAGT ATTCACCATCTCCAGAGACAATGGATCTGGGACAGAATTCACT TCCAAGAACACCCTGTATCTTC CTCACAATCAGCAGCCTGCAGAAATGAACAGCCTGAGAGCCG CCTGAAGATTTTGCAACTTATT AGGACACGGCCGTGTATTACTGACTGTCAACAGCTTAATAGTTA TGCGAGAGAGACCCTAGCCTTT CCCTCCAGCTTTCGGCGGAGGGGACTACTGGGGCCAGGGAACCC ACCAAGGTGGAGATCAAA TGGTCACCGTCTCCTCA PSA-1B9SEQ ID NO: 334 SEQ ID NO: 335 CAGGTGCAGCTGCAGGAGTCGGGACATCGTGATGACCCAGTCTC GCCCAGGACTGGTGAAGCCTTC CAGACTCCCTGGCTGTGTCTCTGGAGACCCTGTCCCTCACCTGC GGGCGAGAGGGCCACCATCAA ACTGTCTCTGGTGGCTCCATCACTGCAAGTCCAGCCAGAGTGTT GTAGTTACTACTGGAGCTGGAT TTATACAGCTCCAACAATAAGCCGGCAGCCCCCAGGGAAGGG AACTACTTAGCTTGGTACCAGC ACTGGAGTGGATTGGGTATATCAGAAACCAGGACAGCCTCCTA TCTTACAGTGGGAGCACCAACT AGCTGCTCATTTACTGGGCATCACAACCCCTCCCTCAAGAGTCG TACCCGGGAATCCGGGGTCCCT AGTCACCATATCACTAGACACGGACCGATTCAGTGGCAGCGGG TCCAAGAACCAGTTCTCCCTGA TCTGGGACAGATTTCACTCTCAAGCTGAGCTCTGTGACCGCTGC CCATCAGCAGCCTGCAGGCTG GGACACGGCCGTGTATTACTGTAAGATGTGGCAGTTTATTACTG GCGAGCAACGGCCAGTATTACG TCAGCAATATTATAGTACTCCGATATTTTGACTGGTCAACCTCCT CTCACTTTCGGCGGAGGGACC GACTACTGGTACTTCGATCTCTAAGGTGGAGATCAAA GGGGCCGTGGCACCCTGGTCAC TGTCTCCTCA P5A-1D1 SEQ ID NO: 344SEQ ID NO: 345 GAGGTGCAGCTGGTGGAGTCTG GACATCCAGTTGACCCAGTCTCGAGGAGGCTTGATCCAGCCTGG CATCCTTCCTGTCTGCATCTGT GGGGTCCCTGAGACTCTCCTGTAGGAGACAGAGTCACCATCAC GCAGCCTCTGGGCTCACCGTCA TTGCCGGGCCAGTCAGGGCATTGTAGCAACTACATGAGCTGGGT AGCAGTTATTTAGCCTGGTATC CCGCCAGGCTCCAGGGAAGGGAGCAAAAACCAGGGAAAGCCC GCTGGAGTGGGTCTCAGTTATT CTAAGCTCCTGATCTATGCTGCTATAGCGGTGGTAGCACATACT ATCCACTTTGCAAAGTGGGGTC ACGCAGACTCCGTGAAGGGCCGCCATCAAGGTTCAGCGGCAGT ATTCACCATCTCCAGAGACAAT GGATCTGGGACAGATTTCACTCTCCAAGAACACGCTGTATCTTC TCACCATCAGCAGCCTGCAGCC AAATGAACAGCCTGAGAGCCGTGAAGATTTTGCAACTTATTAC AGGACACGGCCGTGTATTACTG TGTCAACAGCTTAATAGTTACCTGCGAGAGATTTGTACTACTAC CTACCTTCGGCCAAGGGACAC GGTATGGACGTCTGGGGCCAAGGAC TGGAGATTAAA GGACCACGGTCACCGTCTCCAC A PSA-1D10 SEQ ID NO: 354SEQ ID NO: 355 CAGGTGCAGCTGGTGGAGTCTG CAGTCTGCCCTGACTCAGCCTGGGGGAGGCTTGGTCAAGCCTGG CCTCCGTGTCTGGGTCTCCTGG AGGGTCCCTGAGACTCTCCTGTACAGTCGATCACCATCTCCTGC GCAGCCTCTCAATTCACCTTCA ACTGGAACCAGCAGTGACGTTGTGACTACTCCATGACCTGGAT GGTGGTTATAACTATGTCTCCT CCGCCAGGCTCCAGGGAAGGGGGTACCAACAACACCCAGGCA GCTGGAGTGGGTTTCATACATT AAGCCCCCAAACTCATGATTTAAGTCAAAGTGGTAGTACCATAT TGATGTCAGTAATCGGCCCTCA ACTACGCAGACTCTGTGAAGGGGGGGTTTCTAATCGCTTCTCTG CCGATTCACCATCTCCAGGGAC CCTCCAAGTCTGGCAACACGGAACGCCAAGAACTCACTGTATC CCTCCCTGACCATCTCTGGGCT TGCAAATGAACAGCCTGAGAGCCCAGGCTGAGGACGAGGCTGA CGAGGACACGGCCGTGTATTAC TTATTACTGCAGCTCATTTACATGTGCGAGAGGTGTCAGCCCAT AGCAGCACCACTGTCGTGGTAT CCTACGTTTGGGGGAGTTATCGTCGGCGGAGGGACCAAGCTGA TTCCTTGTACCACTTTGACTACT CCGTCCTAGGGGCCAGGGAACCCTGGTCAC CGTCTCCTCA P5A-2D11 SEQ ID NO: 364 SEQ ID NO: 365GAGGTGCAGCTGGTGCAGTCTG CAGTCTGTGCTGACTCAGCCAC GAGCAGAGGTGAAAAAGCCCGCCTCAGCGTCTGGGACCCCCGG GGGAGTCTCTGAAGATCTCCTG GCAGAGGGTCACCATCTCTTGTTAAGGGTTCTGGATACAGCTTT TCTGGAAGCAGCTCCAACATC ACCAGCTACTGGATCGGCTGGGGGAAGTAATACTGTAAACTGG TGCGCCAGATGCCCGGGAAAGG TACCAGCAGCTCCCAGGAACGCCTGGAGTGGATGGGGATCATC GCCCCCAAACTCCTCATCTATA TATCCTGGTGACTCTGATACCAGTAATAATCAGCGGCCCTCAG GATACAGCCCGTCCTTCCAAGG GGGTCCCTGACCGATTCTCTGGCCAGGTCACCATCTCAGCCGAC CTCCAAGTCTGGCACCTCAGCC AAGTCCATCAGCACCGCCTACCTCCCTGGCCATCAGTGGGCTCC TGCAGTGGAGCAGCCTGAAGGC AGTCTGAGGATGAGGCTGATTCTCGGACACCGCCATGTATTAC ATTACTGTGCAGCATGGGATG TGTGCGAGACGGGATTCGACCTACAGCCTGAATGGTGTGGTATT ACGGTGGTAACACTGACTACTG CGGCGGAGGGACCAAGCTGACGGGCCAGGGAACCCTGGTCACC CGTCCTA GTCTCCTCA P5A-2G9 SEQ ID NO: 374SEQ ID NO: 375 CAGGTGCAGCTGGTGGAGTCTG CAGCCTGTGCTGACTCAGCCACGGGGAGGCGTGGTCCAGCCTGG CTTCCTCCTCCGCATCTCCTGG GAGGTCCCTGAGACTCTCCTGTAGAATCCGCCAGACTCACCTG GCAGCGTCTGGATTCACCTTCA CACCTTGCCCAGTGACATCAATGTAGCTATGGCATGCACTGGGT GTTAGTAGCTACAACATATACT CCGCCAGGCTCCAGGCAAGGGGGGTACCAGCAGAAGCCAGGGA CTGGAGTGGGTGGCAGTTATAT GCCCTCCCAGGTATCTCCTGTAGGTATGATGGAAGTAATAAATA CTACTACTCAGACTCAGATAAG CTATGCAGACTCCGTGAAGGGCGGCCAGGGCTCTGGAGTCCCC CGATTCACCATCTCCAGAGACA AGCCGCTTCTCTGGATCCAAAGATTCCAAGAACACGCTGTATCT ATGCTTCAGCCAATACAGGGA GCAAATGAACAGCCTGAGAGCCTTTTACTCATCTCCGGGCTCCA GAGGACACGGCTGTGTATTACT GTCTGAGGATGAGGCTGACTAGTGCGAGATGGTTCCACACGGG TTACTGTATGATTTGGCCAAGC GGGGTACTTTGACTACTGGGGCAATGCTCTTTATGTCTTCGGAA CAGGGAACCCTGGTCACCGTCT CTGGGACCAAGGTCACCGTCCTCCTCA A PSA-2H3 SEQ ID NO: 384 SEQ ID NO: 385 GAGGTGCAGCTGGTGCAGTCTGCAGTCTGTGCTGACTCAGCCAC GAGCAGAGGTGAAAAAGCCCG CCTCAGCGTCTGGGACCCCCGGGGGAGTCTCTGAAGATCTCCTG GCAGAGGGTCACCATCTCTTGT TAAGGGTTCTGGATACAGCTTTTCTGGAAGCAGCTCCAACATC ACCAGCTACTGGATCGGCTGGG GGAAGTAATACTGTAAACTGGTGCGCCAGATGCCCGGGAAAGG TACCAGCAGCTCCCAGGAACG CCTGGAGTGGATGGGGATCATCGCCCCCAAACTCCTCATCTATA TATCCTGGTGACTCTGATACCA GTAATAATCAGCGGCCCTCAGGATACAGCCCGTCCTTCCAAGG GGGTCCCTGACCGATTCTCTGG CCAGGTCACCATCTCAGCCGAGCTCCAAGTCTGGCACCTCAGCC AAGTCCATCAGCACCGCCTACC TCCCTGGCCATCAGTGGGCTCCTGCAGTGGAGCAGCCTGAAGGC AGTCTGAGGATGAGGCTGATT CTCGGACACCGCCATGTATTACATTACTGTGCAGCATGGGATG TGTGCGAGACGGGATTCGACCT ACAGCCTGAATGGTGTGGTATTACGGTGGTAACACTGACTACTG CGGCGGAGGGACCAAGCTGAC GGGCCAGGGAACCCTGGTCACCCGTCCTA GTCTCCTCA P5A-3A1 SEQ ID NO: 394 SEQ ID NO: 395GAGGTGCAGCTGGTGGAGTCTG GAAATTGTGTTGACGCAGTCTC GAGGAGGCTTGATCCAGCCTGGCAGGCACCCTGTCTTTGTCTCC GGGGTCCCTGAGACTCTCCTGT AGGGGAAAGAGCCACCCTCTCGCAGCCTCTGGGTTCACCGTCA CTGCAGGGCCAGTCAGAGTGT GTAGCAACTACATGAGCTGGGTTAGCAGCAGCTACTTAGCCTGG CCGCCAGGCTCCAGGGAAGGG TACCAGCAGAAACCTGGCCAGGCTGGAGTGGGTCTCAGTTATT GCTCCCAGGCTCCTCATCTATG TATAGCGGTGGTAGCACATACTGTGCATCCAGCAGGGCCACTG ACGCAGACTCCGTGAAGGGCCG GCATCCCAGACAGGTTCAGTGATTCACCATCTCCAGAGACAAT GCAGTGGGTCTGGGACAGACT TCCAAGAACACGCTGTATCTTCTCACTCTCACCATCAGCAGACT AAATGAACAGCCTGAGAGCCG GGAGCCTGAAGATTTTGCAGTAGGACACGGCCGTGTATTACTG GTATTACTGTCAGCAGTATGGT TGCGAGAGACTACGGTGACTTTAGCTCACCTCGCACTTTTGGCC TACTTTGACTACTGGGGCCAGG AGGGGACCAAGCTGGAGATCAGAACCCTGGTCACCGTCTCCTC AA A PSA-3A6 SEQ ID NO: 404 SEQ ID NO: 405GAAGTGCAGCTGGTGGAGTCTG CAGTCTGCCCTGACTCAGCCTG GGGGAGGCTTGGTACAGCCTGGCCTCCGTGTCTGGGTCTCCTGG CAGGTCCCTGAGACTCTCCTGT ACAGTCGATCACCATCTCCTGCGCAGCCTCTGGATTCACCTTTG ACTGGAACCAGCAGTGACGTT ATGATTATGCCATGCACTGGGTGGTGGTTATAACTATGTCTCCT CCGGCAAGCTCCAGGGAAGGG GGTACCAACAACACCCAGGCACCTGGAGTGGGTCTCAGGTATT AAGCCCCCAAACTCATGATTTA AGTTGGAATAGTGGTACCATAGTGATGTCAGTAATCGGCCCTCA GCTATGCGGACTCTGTGAAGGG GGGGTTTCTAATCGCTTCTCTGCCGATTCATCATCTCCAGAGAC GCTCCAAGTCTGGCAACACGG AACGCCAAGAACTCCCTGTATCCCTCCCTGACCATCTCTGGGCT TGCAAATGAACAGTCTGAGAGC CCAGGCTGAGGACGAGGCTGATGAGGACACGGCCTTGTATTAC TTATTACTGCAGCTCATATACA TGTGCAGGGGGTGGTACTATGGAGCAGCAGCACTGTGGTATTC TTCGGGGAGTTATTGCCGGAGG GGCGGAGGGACCAAGCTGACCGGGAACTCATCCGGTGGATGAC GTCCTA TACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGT CTCCTCA P5A-3B4 SEQ ID NO: 414 SEQ ID NO: 415GAGGTGCAGCTGGTGCAGTCTG CAGTCTGTGCTGACTCAGCCAC GAGCAGAGGTGAAAGAGCCCGCCTCAGCGTCTGGGACCCCCGG GGGAGTCTCTGAAGATCTCCTG GCAGAGGGTCACCATCTCTTGTTAAGGGTTCTGGATACAGCTTT TCTGGAAGCAGCTCCAACATC ACCAGCTACTGGATCGGCTGGGGGAAGTAATACTGTAAACTGG TGCGCCAGATGCCCGGGAAAGG TACCAGCAGCTCCCAGGAACGCCTGGAGTGGATGGGGATCATC GCCCCCAAACTCCTCATCTATA TATCCTGGTGACTCTGATACCAGTAATAATCAGCGGCCCTCAG GATACAGCCCGTCCTTCCAAGG GGGTCCCTGACCGATTCTCTGGCCAGGTCACCATCTCAGCCGAC CTCCAAGTCTGGCACCTCAGCC AAGTCCATCAGCACCGCCTACCTCCCTGGCCATCAGTGGGCTCC TGCAGTGGAGCAGCCTGAAGGC AGTCTGAGGATGAGGCTGATTCTCGGACACCGCCATGTATTAC ATTACTGTGCAGCATGGGATG TGTGCGAGACGGGATTCGACCTACAGCCTGAATGGTGTGGTATT ACGGTGGTAACACTGACTACTG CGGCGGAGGGACCAAGCTGACGGGCCAGGGAACCCTGGTCACC CGTCCTA GTCTCCTCA PSA-3C12 SEQ ID NO: 424SEQ ID NO: 425 CAGATCACCTTGAAGGAGTCTG GACATCGTGATGACCCAGTCTCGTCCTACGCTGGTGAAACCCAC CAGACTCCCTGGCTGTGTCTCT ACAGACCCTCACGCTGACCTGCGGGCGAGAGGGCCACCATCAA ACCTTCTCTGGGTTCTCACTCAG CTGCAAGTCCAGCCAGAGTGTTCACTAGTGGAGTGGGTGTGGGC TTATACAGCTCCAACAATAAG TGGATCCGTCAGCCCCCAGGAAAACTACTTAGCTTGGTACCAGC AGGCCCTGGAGTGGCTTGCACT AGAAACCAGGACAGCCTCCTACATTTATTGGGATGATGATAAG AGCTGCTCATTTACTGGGCATC CGCTACAGCCCATCTCTGAAGATACCCGGGAATCCGGGGTCCCT GCAGGCTCACCATCACCAAGGA GACCGATTCAGTGGCAGCGGGCACCTCCAAAAACCAGGTGGTC TCTGGGACAGATTTCACTCTCA CTTACAATGACCAACATGGACCCCATCAGCAGCCTGCAGGCTG CTGTGGACACAGCCACATATTA AAGATGTGGCAGTTTATTACTGCTGTGCACACAGTTTGTTTCTCA TCAGCAATATTATAGTACTCCT CGGTAGGGTATAGCAGCAGCTGCACACTTTTGGCCAGGGGACC GTCCCCTTTTGACTACTGGGGC AAGCTGGAGATCAAACAGGGAACCCTGGTCACCGTCT CCTCA P22A-1D1 SEQ ID NO: 434 SEQ ID NO: 435GAGGTGCAGCTGGTGGAGTCTG GACATCCAGTTGACCCAGTCTC GAGGAGGCTTGATCCAGCCTGGCATCCTTCCTGTCTGCATCTGT GGGGTCCCTGAGACTCTCCTGT AGGAGACAGAGTCACCATCACGCAGCCTCTGGGTTCACCGTCA TTGCCGGGCCAGTCAGGGCATT GTAGCAACTACATGAGCTGGGTAGCAGTTATTTAGCCTGGTATC CCGCCAGGCTCCAGGGAAGGG AGCAAAAACCAGGGAAAGCCCGCTGGAGTGGGTCTCAGTTATT CTAAGCTCCTGATCTATGCTGC TATAGCGGTGGTAGCACATACTATCCACTTTGCAAAGTGGGGTC ACGCAGACTCCGTGAAGGGCCG CCATCAAGGTTTAGCGGCAGTATTCACCATCTCCAGAGACAAT GGATCTGGGACAGAATTCACT TCCAAGAACACGCTGTATCTTCCTCACAATCAGCAGCCTGCAG AAATGAACAGCCTGAGAGCCG CCTGAAGATTTTGCAACTTATTAGGACACGGCCGTGTATTACTG ACTGTCTACACCTTAATAGTTA TGCGAGAGATCGAGACTACTACCAGGACGTTCGGCCTAGGGAC GGTATGGACGTCTGGGGCCAAG CAAGGTGGAAATCAAAGGACCACGGTCACCGTCTCCTC A

In certain embodiments, the antibodies or the antigen-binding fragmentsthereof provided herein further comprise an immunoglobulin (Ig) constantregion, which optionally further comprises a heavy chain and/or a lightchain constant region. In certain embodiments, the heavy chain constantregion comprises CH1, hinge, and/or CH2-CH3 regions (or optionallyCH2-CH3-CH4 regions). In certain embodiments, the antibodies or theantigen-binding fragments thereof provided herein comprises heavy chainconstant regions of human IgG1, IgG2, IgG3, IgG4, IgA1, IgA2 or IgM. Incertain embodiments, the light chain constant region comprises Cκ or Cλ.The constant region of the antibodies or the antigen-binding fragmentsthereof provided herein may be identical to the wild-type constantregion sequence or be different in one or more mutations.

In certain embodiments, the heavy chain constant region comprises an Fcregion. Fc region is known to mediate effector functions such asantibody-dependent cellular cytotoxicity (ADCC), Antibody-dependentcellular phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC)of the antibody. Fc regions of different Ig isotypes have differentabilities to induce effector functions. For example, Fc regions of IgG1and IgG3 have been recognized to induce both ADCC and CDC moreeffectively than those of IgG2 and IgG4. In certain embodiments, theantibodies and antigen-binding fragments thereof provided hereincomprises an Fc region of IgG1, or IgG3 isotype, which could induce ADCCor CDC. Alternatively, the antibodies and antigen-binding fragmentsthereof provided herein comprise a constant region of IgG4 or IgG2isotype, which has reduced or depleted effector function. In certainembodiments, the anti-SARS-COV-2 antibodies or antigen-binding fragmentsthereof comprises a wild type human IgG1 Fc region comprising thesequence of SEQ ID NO: 115 or other wild type human IgG1 alleles.

Table 4 shows the amino acid sequences for the heavy chain and lightchain constant regions of the monoclonal antibodies: P2A-1A8, P2A-1A9,P2A-1A10, P2A-1B3, P2B-2F6, P2B-2G4, P2B-2G11, P2C-1A3, P2C-1C8,P2C-1C10, P2C-1D5, P2C-1F11, P2B-1G5, P2B- 1A1, P2C-1D7, P2B-1A10,P2B-1D9, P2B-1E4, P2B-1G1, P4A-2D9, P5A-2G7, P5A-3C8, P5A-1D2, P5A-2F11,P5A-2E1, P5A-1C8, P1A-1C10, P4A-1H6, P4B-1F4, P5A-1B6, P5A- 1B8,P5A-1B9, P5A-1D1, P5A-1D10, P5A-2D11, P5A-2G9, P5A-2H3, P5A-3A1,P5A-3A6, P5A-3B4, P5A-3C12, and P22A-1D1 wherein the antibodies P2A-1A8,P2A-1A9, P2B-2F6, P2B-2G4, P2B-2G11, P2C-1D5, P2B-1G5, P2B-1A1, P2B-1D9,P2B-1E4, P5A-2G7, P5A-1D2, P5A-2E1, P5A-1D10, P5A-2D11, P5A-2G9,P5A-2H3, P5A-3A6, and P5A-3B4 have lambda light chains (with a lambdalight chain constant region sequence of SEQ ID NO: 116), the antibodiesP2A-1A10, P2A-1B3, P2C-1A3, P2C-1C8, P2C-1C10, P2C-1F11, P2C-1D7,P2B-1A10, P2B-1G1, P4A-2D9, P5A-3C8, P5A-2F11, P5A-1C8, P1A-1C10,P4A-1H6, P4B- 1F4, P5A-1B6, P5A-1B8, P5A-1B9, P5A-1D1, P5A-3A1,P5A-3C12, and P22A-1D1 have kappa light chains (with a kappa light chainconstant region sequence of SEQ ID NO: 117), and all 42 antibodies havethe same heavy chain constant region (SEQ ID NO: 115).

TABLE 4 Amino acid and nucleic acid sequences of constant regions HCAmino SEQ ID NO: 115 (Heavy acid ASTKGPSVFPLAPSSKSTSGGTAALGCLVK ChainDYFPEPVTVSWNSGALTSGVHTFPAVLQSS constant GLYSLSSVVTVPSSSLGTQTYICNVNHKPSregion) NTKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK NucleicSEQ ID NO: 118 Acid GCGTCGACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGG GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCCGTGACGGTGTCG TGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACC TACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCC AAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGA CCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCT GAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGG TACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAAC AGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCC AAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAG CTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTG CTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGG CAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACG CAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LC AminoSEQ ID NO: 116 (lambda acid GQPKAAPSVTLFPPSSEELQANKATLVCLI ChainSDFYPGAVTVAWKADSSPVKAGVETTTPSK constant QSNNKYAASSYLSLTPEQWKSHRSYSCQVTregion) HEGSTVEKTVAPTECS Nucleic SEQ ID NO: 119 AcidGGTCAGCCCAAGGCTGCCCCCTCGGTCACT CTGTTCCCACCCTCGAGTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATA AGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAG GCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGC TACCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACG CATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA KC Amino SEQ ID NO: 117 (kappa acidRTVAAPSVFIFPPSDEQLKSGTASVVCLLN Chain NFYPREAKVQWKVDNALQSGNSQESVTEQDconstant SKDSTYSLSSTLTLSKADYEKHKVYACEVT region) HQGLSSPVTKSFNRGECNucleic SEQ ID NO: 120 Acid CGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCT GGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTACCCCAGAGAAGCCAAAGTGCAG TGGAAGGTGGACAACGCCCTGCAGAGCGGAAACAGCCAGGAAAGCGTGACAGAGCAGGAT TCCAAGGATTCCACATACAGCCTGAGCAGCACACTGACACTGTCCAAGGCCGACTACGAG AAGCACAAGGTGTACGCCTGCGAAGTGACACACCAGGGACTGTCCTCCCCTGTGACAAAG AGCTTCAACAGAGGAGAATGC

In some embodiments, signal peptide may be added when expressing theantibodies of the present disclosure, these signal peptides may bepartially or full removed by host cells during the secretion of theantibody. In certain embodiments, for expressing the 26 exemplaryantibodies of the present disclosure, signal peptide (SEQ ID NO: 130:MGWSCIILFLVATATGVHS) is included when expressing the heavy chain, signalpeptide (SEQ ID NO: 131: MGWSCIILFLVATATGSWA) is included whenexpressing the light chain.

Table 11 which is appended at the end of the specification showssequences and SEQ ID NOs mentioned or used in the present application.

Antibody Variants

In certain embodiments, the antibody or antigen binding fragmentsthereof provided herein comprise one or more mutations in one or more ofthe CDR sequences provided in Table 1 above, one or more of the non-CDRsequences of the heavy chain variable region or light chain variableregion provided in Table 2, and/or the constant region (e.g. Fc region)in Table 4, yet retaining specific binding affinity to RBD of spikeprotein of SARS-CoV-2. These are also referred to as variants ofantibodies P2A-1A8, P2A-1A9, P2B-2G11, P2A-1A10, P2A-1B3, P2B-2F6,P2B-2G4, P2C-1A3, P2C-1C8, P2C-1C10, P2C-1D5, P2C-1F11, P2B-1G5,P2B-1A1, P2C-1D7, P2B-1A10, P2B-1D9, P2B-1E4, P2B-1G1, P4A-2D9, P5A-2G7,P5A-3C8, P5A-1D2, P5A-2F11, P5A-2E1, P5A-1C8, P1A-1C10, P4A-1H6,P4B-1F4, P5A-1B6, P5A-1B8, P5A-1B9, P5A-1D1, P5A-1D10, P5A-2D11,P5A-2G9, P5A-2H3, P5A- 3A1, P5A-3A6, P5A-3B4, P5A-3C12, P22A-1D1, or theantigen binding fragments thereof. “Mutations” or “mutated” as usedherein include substitutions, insertions, and/or deletions in an aminoacid sequence or polynucleotide sequence. In certain embodiments, atleast one (or all) of the mutation(s) comprises a conservativesubstitution.

In certain embodiments, the variants comprise 1, 2, or 3 CDR sequenceshaving at least 80% (e.g. at least 85%, 88%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99%) sequence identity to that (or those) listed inTable 1 above, and in the meantime retain the binding specificity toSARS-COV-2, optionally having binding affinity at a level similar to oreven higher than its parent antibody.

In certain embodiments, the variants comprise one or more variableregion sequences having at least 80% (e.g. at least 85%, 88%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%) sequence identity to that (orthose) listed in Table 2 above, and in the meantime retain the bindingspecificity to SARS-COV-2, optionally having binding affinity toSARS-COV-2 at a level similar to or even higher than its parentantibody. In some embodiments, a total of 1 to 10 amino acids have beenmutated in a variable region sequence listed in Table 2 above. In someembodiments, the mutations occur in the non-CDR sequences (e.g. in theFRs). In some embodiments, the mutations are conservative substitutions.

In certain embodiments, the present disclosure provides a variant ofantibody P2A-1A8, P2A-1A9, P2B-2G11, P2A-1A10, P2A-1B3, P2B-2F6,P2B-2G4, P2C-1A3, P2C-1C8, P2C-1C10, P2C-1D5, P2C-1F11, P2B-1G5,P2B-1A1, P2C-1D7, P2B-1A10, P2B-1D9, P2B- 1E4, P2B-1G1, P4A-2D9,P5A-2G7, P5A-3C8, P5A-1D2, P5A-2F11, P5A-2E1, P5A-1C8, P1A-1C10,P4A-1H6, P4B-1F4, P5A-1B6, P5A-1B8, P5A-1B9, P5A-1D1, P5A-1D10, P5A-2D11, P5A-2G9, P5A-2H3, P5A-3A1, P5A-3A6, P5A-3B4, P5A-3C12, orP22A-1D1, wherein the variant comprises:

a) a heavy chain CDR1 (HCDR1) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to a HCDR1 sequence of the parent antibody listed inTable 1, and/or

b) a heavy chain CDR2 (HCDR2) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to a HCDR2 sequence of the parent antibody listed inTable 1, and/or

c) a heavy chain CDR3 (HCDR3) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to a HCDR3 sequence of the parent antibody listed inTable 1, and/or

d) a light chain CDR1 (LCDR1) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to a LCDR1 sequence of the parent antibody listed inTable 1, and/or

e) a light chain CDR2 (LCDR2) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to a LCDR2 sequence of the parent antibody listed inTable 1, and/or

f) a light chain CDR3 (LCDR3) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to a LCDR3 sequence of the parent antibody listed inTable 1, and

in the meantime retain the binding specificity to SARS-COV-2, optionallyhaving binding affinity to SARS-COV-2 at a level similar to or evenhigher than its parent antibody.

In certain embodiments, the antibody variants provided herein comprisesan HCDR1 having no more than 3, 2, or 1 amino acid mutations in a HCDR1sequence of the parent antibody listed in Table 1, an HCDR2 having nomore than 6, 5, 4, 3, 2, or 1 amino acid mutations in a HCDR2 sequenceof the parent antibody listed in Table 1, HCDR3 having no more than 6,5, 4, 3, 2, or 1 amino acid mutations in a HCDR3 sequence of the parentantibody listed in Table 1, LCDR1 having no more than 2 or 1 amino acidmutations in a LCDR1 sequence of the parent antibody listed in Table 1,LCDR2 having no more than 3, 2, or 1 amino acid mutations in a LCDR2sequence of the parent antibody listed in Table 1, and/or LCDR3 havingno more than 3, 2, or 1 amino acid mutations in a LCDR3 sequence of theparent antibody listed in Table 1, and in the meantime retain thebinding specificity to SARS-COV-2, optionally having binding affinity toSARS-COV-2 at a level similar to or even higher than its parentantibody.

In certain embodiments, the antibody variants provided herein comprises:

a) at least one heavy chain CDR sequence having no more than 3, 2, or 1amino acid substitutions in a heavy chain CDR sequence of the parentantibody listed in Table 1, or

b) at least two heavy chain CDR sequences each having no more than 3, 2,or 1 amino acid substitutions in a heavy chain CDR sequence of theparent antibody listed in Table 1, or

c) three heavy chain CDR sequences each having no more than 3, 2, or 1amino acid substitutions in a heavy chain CDR sequence of the parentantibody listed in Table 1, or

d) at least one light chain sequence having no more than 3, 2, or 1amino acid substitutions in a heavy chain CDR sequence of the parentantibody listed in Table 1, or

e) at least two light chain CDR sequences each having no more than 3, 2,or 1 amino acid substitutions in a heavy chain CDR sequence of theparent antibody listed in Table 1, or

f) three light chain CDR sequences each having no more than 3, 2, or 1amino acid substitutions in a heavy chain CDR sequence of the parentantibody listed in Table 1, and

in the meantime retains the binding specificity to SARS-COV-2,optionally having binding affinity at a level similar to or even higherthan its parent antibody.

In certain embodiments, the antibody variants provided herein retains atleast part of (or the entirety of) the paratope of their parentantibodies. As used herein, the term “paratope” with respect to anantibody refers to a group of amino acid residues on the variableregions of the antibody that makes direct contact with the antigen andform the antigen binding site of the variable regions. A paratopenormally comprises or consists of amino acid residues in one or more CDRsequences.

In certain embodiments, the present disclosure provides variants ofantibody P2B-2F6, wherein the variant comprises:

a) a heavy chain CDR1 (HCDR1) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 41, and/or

b) a heavy chain CDR2 (HCDR2) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 42, and/or

c) a heavy chain CDR3 (HCDR3) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 43, and/or

d) a light chain CDR1 (LCDR1) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 44, and/or

e) a light chain CDR2 (LCDR2) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 45, and/or

f) a light chain CDR3 (LCDR3) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 46, and

in the meantime retain the binding specificity to SARS-COV-2, optionallyhaving binding affinity to SARS-COV-2 at a level similar to or evenhigher than antibody P2B-2F6.

In certain embodiments, the antibody variants of antibody P2B-2F6comprises an HCDR1 having no more than 4, 3, 2, or 1 amino acidmutations in SEQ ID NO: 41, an HCDR2 having no more than 3, 2, or 1amino acid mutations in SEQ ID NO: 42, HCDR3 having no more than 6, 5,4, 3, 2, or 1 amino acid substitutions in SEQ ID NO: 43, LCDR1 having nomore than 4, 3, 2, or 1 amino acid mutations in SEQ ID NO: 44, LCDR2having no more than 3, 2, or 1 amino acid mutations in SEQ ID NO: 45,and/or LCDR3 having no more than 4, 3, 2, or 1 amino acid mutations inSEQ ID NO: 46, and in the meantime retain the binding specificity toSARS-COV-2, optionally having binding affinity to SARS-COV-2 at a levelsimilar to or even higher than antibody P2B-2F6.

In certain embodiments, the variants of antibody P2B-2F6 retain theentirety of the paratope of antibody P2B-2F6 while one or more of theamino acid residues outside the paratope of the antibody may be mutated.In certain embodiments, the paratope of antibody P2B-2F6 comprises orconsists of: Y27, S28, S30, S31, and Y33 of HCDR1; H54 of HCDR2; G102,I103, V105, V106 and P107 of HCDR3; and/or G31, Y32 and N33 of LCDR1;wherein the numbering of residues in the heavy chain CDRs is accordingto SEQ ID NO: 47, and the numbering of residues in the light chain CDRis according to SEQ ID NO: 48.

In certain embodiments, the variants of antibody P2B-2F6 retain at leastpart of the paratope of antibody P2B-2F6. For example, the variants ofantibody P2B-2F6 retain at least 60%, at least 70%, at least 80%, or atleast 90% of the residues of the paratope of antibody P2B-2F6. Incertain embodiments, the variants of antibody P2B-2F6 comprises one ormore mutations (e.g. conservative substitutions) in the paratope ofantibody P2B-2F6. In certain embodiments, the variants of antibodyP2B-2F6 comprises no more than 5, 4, 3, 2 or 1 mutations (e.g.substitutions) in the paratope of antibody P2B-2F6. In certainembodiments, the variants of antibody P2B-2F6 comprises no more than 5,4, 3, 2 or 1 conservative substitutions in the paratope of antibodyP2B-2F6.

In certain embodiments, the present disclosure provides variants ofantibody P2C-1F11, wherein the variant comprises:

a) a heavy chain CDR1 (HCDR1) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 105, and/or

b) a heavy chain CDR2 (HCDR2) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 106, and/or

c) a heavy chain CDR3 (HCDR3) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 107, and/or

d) a light chain CDR1 (LCDR1) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 108, and/or

e) a light chain CDR2 (LCDR2) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 109, and/or

f) a light chain CDR3 (LCDR3) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 110, and

in the meantime retain the binding specificity to SARS-COV-2, optionallyhaving binding affinity to SARS-COV-2 at a level similar to or evenhigher than antibody P2C-1F11.

In certain embodiments, the antibody variants of antibody P2C-1F11comprises an HCDR1 having no more than 4, 3, 2, or 1 amino acidmutations in SEQ ID NO: 105, an HCDR2 having no more than 3, 2, or 1amino acid mutations in SEQ ID NO: 106, HCDR3 having no more than 6, 5,4, 3, 2, or 1 amino acid mutations in SEQ ID NO: 107, LCDR1 having nomore than 4, 3, 2, or 1 amino acid mutations in SEQ ID NO: 108, LCDR2having no more than 3, 2, or 1 amino acid mutations in SEQ ID NO: 109,and/or LCDR3 having no more than 4, 3, 2, or 1 amino acid mutations inSEQ ID NO: 110, and in the meantime retain the binding specificity toSARS-COV-2, optionally having binding affinity to SARS-COV-2 at a levelsimilar to or even higher than antibody P2C-1F11.

In certain embodiments, the variants of antibody P2C-1F11 retain theentirety of the paratope of antibody P2C-1F11 while one or more of theamino acid residues outside the paratope of the antibody may be mutated.In certain embodiments, the paratope of antibody P2C-1F11 comprises orconsists of: G26, 127, T28, S31, N32 and Y33 of HCDR1; Y52, S53, G54,and S56 of HCDR2; R97, L99, V100, V101, Y102 and D105 of HCDR3; and/orS28, S30 and Y33 of LCDR1; wherein the numbering of residues in heavychain is according to SEQ ID NO: 111, and the numbering of residues inlight chain CDR is according to SEQ ID NO: 112.

In certain embodiments, the variants of antibody P2C-1F11 retain atleast part of the paratope of antibody P2C-1F11. For example, thevariants of antibody P2C-1F11 retain at least 60%, at least 70%, atleast 80%, or at least 90% of the residues of the paratope of antibodyP2C-1F11. In certain embodiments, the variants of antibody P2C-1F11comprises one or more mutations or substitutions (e.g. conservativesubstitutions) in the paratope of antibody P2C-1F11. In certainembodiments, the variants of antibody P2C-1F11 comprises no more than 6,5, 4, 3, 2 or 1 mutations (e.g. substitutions) in the paratope ofantibody P2C-1F11. In certain embodiments, the variants of antibodyP2C-1F11 comprises no more than 6, 5, 4, 3, 2 or 1 conservativesubstitutions in the paratope of antibody P2C-1F11.

In certain embodiments, the present disclosure provides variants ofantibody P22A-1D1, wherein the variant comprises:

a) a heavy chain CDR1 (HCDR1) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 426, and/or

b) a heavy chain CDR2 (HCDR2) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 427, and/or

c) a heavy chain CDR3 (HCDR3) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 428, and/or

d) a light chain CDR1 (LCDR1) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 429, and/or

e) a light chain CDR2 (LCDR2) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 430, and/or

f) a light chain CDR3 (LCDR3) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 431, and

in the meantime retain the binding specificity to SARS-COV-2, optionallyhaving binding affinity to SARS-COV-2 at a level similar to or evenhigher than antibody P22A-1D1.

In certain embodiments, the antibody variants of antibody P22A-1D1comprises an HCDR1 having no more than 6, 5, 4, 3, 2, or 1 amino acidmutations in SEQ ID NO: 426, an HCDR2 having no more than 5, 4, 3, 2, or1 amino acid mutations in SEQ ID NO: 427, HCDR3 having no more than 6,5, 4, 3, 2, or 1 amino acid substitutions in SEQ ID NO: 428, LCDR1having no more than 5, 4, 3, 2, or 1 amino acid mutations in SEQ ID NO:429, LCDR2 having no more than 3, 2, or 1 amino acid mutations in SEQ IDNO: 430, and/or LCDR3 having no more than 4, 3, 2, or 1 amino acidmutations in SEQ ID NO: 431, and in the meantime retain the bindingspecificity to SARS-COV-2, optionally having binding affinity toSARS-COV-2 at a level similar to or even higher than antibody P22A-1D1.

In certain embodiments, the variants of antibody P22A-1D1 retain theentirety of the paratope of antibody P22A-1D1 while one or more of theamino acid residues outside the paratope of the antibody may be mutated.In certain embodiments, the paratope of antibody P22A-1D1 comprises orconsists of: G26, F27, T28, S31, N32 and Y33 of HCDR1; Y52, S53, G54,and S56 of HCDR2; Y58 of heavy chain framework region 3, R97, R99, D100,Y101, Y102 and D105 of HCDR3; Q27, G28, 129, S30 and Y32 of LCDR1; S67of LCDR2; and/or H90, L91, N92 and Y94 of LCDR3; wherein the numberingof residues in the heavy chain CDRs is according to SEQ ID NO: 432, andthe numbering of residues in the light chain CDR is according to SEQ IDNO: 433.

In certain embodiments, the variants of antibody P22A-1D1 retain atleast part of the paratope of antibody P22A-1D1. For example, thevariants of antibody P22A-1D1 retain at least 60%, at least 70%, atleast 80%, or at least 90% of the residues of the paratope of antibodyP22A-1D1. In certain embodiments, the variants of antibody P22A-1D1comprises one or more mutations (e.g. conservative substitutions) in theparatope of antibody P22A-1D1. In certain embodiments, the variants ofantibody P22A-1D1 comprises no more than 5, 4, 3, 2 or 1 mutations (e.g.substitutions) in the paratope of antibody P22A-1D1. In certainembodiments, the variants of antibody P22A-1D1 comprises no more than 5,4, 3, 2 or 1 conservative substitutions in the paratope of antibodyP22A-1D1.

In certain embodiments, the present disclosure provides variants ofantibody P5A-1D2, wherein the variant comprises:

a) a heavy chain CDR1 (HCDR1) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 236, and/or

b) a heavy chain CDR2 (HCDR2) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 237, and/or

c) a heavy chain CDR3 (HCDR3) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 238, and/or

d) a light chain CDR1 (LCDR1) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 239, and/or

e) a light chain CDR2 (LCDR2) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 240, and/or

f) a light chain CDR3 (LCDR3) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 241, and

in the meantime retain the binding specificity to SARS-COV-2, optionallyhaving binding affinity to SARS-COV-2 at a level similar to or evenhigher than antibody P5A-1D2.

In certain embodiments, the antibody variants of antibody P5A-1D2comprises an HCDR1 having no more than 6, 5, 4, 3, 2, or 1 amino acidmutations in SEQ ID NO: 236, an HCDR2 having no more than 9, 8, 7, 6, 5,4, 3, 2, or 1 amino acid mutations in SEQ ID NO: 237, HCDR3 having nomore than 6, 5, 4, 3, 2, or 1 amino acid substitutions in SEQ ID NO:238, LCDR1 having no more than 4, 3, 2, or 1 amino acid mutations in SEQID NO: 239, LCDR2 having no more than 4, 3, 2, or 1 amino acid mutationsin SEQ ID NO: 240, and/or LCDR3 having no more than 4, 3, 2, or 1 aminoacid mutations in SEQ ID NO: 241, and in the meantime retain the bindingspecificity to SARS-COV-2, optionally having binding affinity toSARS-COV-2 at a level similar to or even higher than antibody P5A-1D2.

In certain embodiments, the variants of antibody P5A-1D2 retain theentirety of the paratope of antibody P5A-1D2 while one or more of theamino acid residues outside the paratope of the antibody may be mutated.In certain embodiments, the paratope of antibody P5A-1D2 comprises orconsists of: G26, F27, 128, S31, N32 and Y33 of HCDR1; Y52, S53, G54,and S56 of HCDR2; Y58 and R87 of heavy chain framework region 3, R97,L99, Q100, V101, G102, A103, T104 and D106 of HCDR3; A31 and Y33 ofLCDR1; and/or S95 of LCDR3; wherein the numbering of residues in theheavy chain CDRs is according to SEQ ID NO: 242, and the numbering ofresidues in the light chain CDR is according to SEQ ID NO: 243.

In certain embodiments, the variants of antibody P5A-1D2 retain at leastpart of the paratope of antibody P5A-1D2. For example, the variants ofantibody P5A-1D2 retain at least 60%, at least 70%, at least 80%, or atleast 90% of the residues of the paratope of antibody P5A-1D2. Incertain embodiments, the variants of antibody P5A-1D2 comprises one ormore mutations (e.g. conservative substitutions) in the paratope ofantibody P5A-1D2. In certain embodiments, the variants of antibodyP5A-1D2 comprises no more than 5, 4, 3, 2 or 1 mutations (e.g.substitutions) in the paratope of antibody P5A-1D2. In certainembodiments, the variants of antibody P5A-1D2 comprises no more than 5,4, 3, 2 or 1 conservative substitutions in the paratope of antibodyP5A-1D2.

In certain embodiments, the present disclosure provides variants ofantibody P5A-3C8, wherein the variant comprises:

a) a heavy chain CDR1 (HCDR1) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 226, and/or

b) a heavy chain CDR2 (HCDR2) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 227, and/or

c) a heavy chain CDR3 (HCDR3) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 228, and/or

d) a light chain CDR1 (LCDR1) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 229, and/or

e) a light chain CDR2 (LCDR2) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 230, and/or

f) a light chain CDR3 (LCDR3) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 231, and

in the meantime retain the binding specificity to SARS-COV-2, optionallyhaving binding affinity to SARS-COV-2 at a level similar to or evenhigher than antibody P5A-3C8.

In certain embodiments, the antibody variants of antibody P5A-3C8comprises an HCDR1 having no more than 6, 5, 4, 3, 2, or 1 amino acidmutations in SEQ ID NO: 226, an HCDR2 having no more than 5, 4, 3, 2, or1 amino acid mutations in SEQ ID NO: 227, HCDR3 having no more than 6,5, 4, 3, 2, or 1 amino acid substitutions in SEQ ID NO: 228, LCDR1having no more than 5, 4, 3, 2, or 1 amino acid mutations in SEQ ID NO:229, LCDR2 having no more than 3, 2, or 1 amino acid mutations in SEQ IDNO: 230, and/or LCDR3 having no more than 5, 4, 3, 2, or 1 amino acidmutations in SEQ ID NO: 231, and in the meantime retain the bindingspecificity to SARS-COV-2, optionally having binding affinity toSARS-COV-2 at a level similar to or even higher than antibody P5A-3C8.

In certain embodiments, the variants of antibody P5A-3C8 retain theentirety of the paratope of antibody P5A-3C8 while one or more of theamino acid residues outside the paratope of the antibody may be mutated.In certain embodiments, the paratope of antibody P5A-3C8 comprises orconsists of: G26, F27, T28, S31, N32 and Y33 of HCDR1; Y52, S53, G54,and S56 of HCDR2; Y58 of heavy chain framework region 3, R97, L99, Q100,E101 and H102 of HCDR3; and G28, 129, S30, S31 and Y32 of LCDR1; S67 ofLCDR2; G68 of light chain framework region 3, H90, L91, N92, S93 and Y94of LCDR3; wherein the numbering of residues in the heavy chain CDRs isaccording to SEQ ID NO: 232, and the numbering of residues in the lightchain CDR is according to SEQ ID NO: 233.

In certain embodiments, the variants of antibody P5A-3C8 retain at leastpart of the paratope of antibody P5A-3C8. For example, the variants ofantibody P5A-3C8 retain at least 60%, at least 70%, at least 80%, or atleast 90% of the residues of the paratope of antibody P5A-3C8. Incertain embodiments, the variants of antibody P5A-3C8 comprises one ormore mutations (e.g. conservative substitutions) in the paratope ofantibody P5A-3C8. In certain embodiments, the variants of antibodyP5A-3C8 comprises no more than 5, 4, 3, 2 or 1 mutations (e.g.substitutions) in the paratope of antibody P5A-3C8. In certainembodiments, the variants of antibody P5A-3C8 comprises no more than 5,4, 3, 2 or 1 conservative substitutions in the paratope of antibodyP5A-3C8.

The variants of the antibodies or the antigen binding fragments thereofcan retain their parent antibodies' binding specificity to RBD of thespike protein of SARS-CoV-2, or may further have one or more desirableproperties conferred by the mutation(s). For example, the variants mayhave improved antigen-binding affinity, improved glycosylation pattern,reduced risk of glycosylation, reduced deamination, reduced or depletedeffector function(s), improved FcRn receptor binding in a pH dependentmanner, increased pharmacokinetic half-life, pH sensitivity, and/orcompatibility to conjugation (e.g. one or more introduced cysteineresidues). Such variants are also known as affinity variants,glycosylation variants, cysteine variants, Fc variants, and so on, whichare described in more details as follows.

a) Affinity Variant

Affinity variant may contain modifications or substitutions in one ormore CDR sequences as provided in Table 1 above, one or more framework(FR) sequences provided herein, or the heavy or light chain variableregion sequences provided in Table 2 above. FR sequences can be readilyidentified by a skilled person in the art based on the CDR sequences inTable 1 above and variable region sequences in Table 2 above, as it iswell-known in the art that a CDR region is flanked by two FR regions inthe variable region.

The affinity variants retain specific binding affinity to RBD of thespike protein of SARS-COV-2 of the parent antibody, or even haveimproved specific binding affinity to the RBD of the spike protein ofSARS-CoV-2 over the parent antibody. Various methods known in the artcan be used to achieve this purpose. For example, a library of antibodyvariants (such as Fab or scFv variants) can be generated and expressedwith phage display technology, and then screened for the bindingaffinity to the RBD of the spike protein of SARS-COV-2. For anotherexample, computer software can be used to virtually simulate the bindingof the antibodies to the RBD of the spike protein of SARS-COV-2, andidentify the amino acid residues on the antibodies which form thebinding interface. Such residues may be either avoided in thesubstitution so as to prevent reduction in binding affinity, or targetedfor substitution to provide for a stronger binding.

In certain embodiments, the affinity variant provided herein comprisesone or more amino acid residue substitutions in one or more CDRsequences, and/or one or more FR sequences. In certain embodiments, anaffinity variant comprises no more than 20, 15, 10, 9, 8, 7, 6, 5, 4, 3,2, or 1 substitutions in the CDR sequences and/or FR sequences in total.

b) Glycosylation Variant

The anti-SARS-COV-2 antibodies and antigen-binding fragments providedherein also encompass a glycosylation variant, which can be obtained toeither increase or decrease the extent of glycosylation of the antibodyor antigen binding fragment thereof.

The antibody or antigen binding fragment thereof may comprise one ormore modifications that introduces or removes a glycosylation site. Aglycosylation site is an amino acid residue with a side chain to which acarbohydrate moiety (e.g. an oligosaccharide structure) can be attached.Glycosylation of antibodies is typically either N-linked or O-linked.N-linked refers to the attachment of the carbohydrate moiety to the sidechain of an asparagine residue, for example, an asparagine residue in atripeptide sequence such as asparagine-X-serine andasparagine-X-threonine, where X is any amino acid except proline.O-linked glycosylation refers to the attachment of one of the sugarsN-aceylgalactosamine, galactose, or xylose to a hydroxyamino acid, mostcommonly to serine or threonine. Removal of a native glycosylation sitecan be conveniently accomplished, for example, by altering the aminoacid sequence such that one of the above-described tripeptide sequences(for N-linked glycosylation sites) or serine or threonine residues (forO-linked glycosylation sites) present in the sequence in the issubstituted. A new glycosylation site can be created in a similar way byintroducing such a tripeptide sequence or serine or threonine residue.

In certain embodiments, the anti-SARS-COV-2 antibodies andantigen-binding fragments provided herein comprise a mutation at N297(e.g. N297A, N297Q, or N297G) to remove the glycosylation site.

c) Cysteine-Engineered Variant

The anti-SARS-COV-2 antibodies and antigen-binding fragments providedherein also encompass a cysteine-engineered variant, which comprises oneor more introduced free cysteine amino acid residues.

A free cysteine residue is one which is not part of a disulfide bridge.A cysteine-engineered variant is useful for conjugation with forexample, a cytotoxic and/or imaging compound, a label, or aradioisoptype among others, at the site of the engineered cysteine,through for example a maleimide or haloacetyl. Methods for engineeringantibodies or antigen-binding fragments thereof to introduce freecysteine residues are known in the art, see, for example, WO2006/034488.

d) Fc Variant

The anti-SARS-COV-2 antibodies and antigen-binding fragments providedherein also encompass an Fc variant, which comprises one or more aminoacid residue modifications or substitutions at its Fc region and/orhinge region, for example, to provide for altered effector functionssuch as ADCC, ADCP and CDC. Methods of altering ADCC activity byantibody engineering have been described in the art, see for example,Shields R L. et al., J Biol Chem. 2001. 276(9): 6591-604; Idusogie E E.et al., J Immunol. 2000.164(8):4178-84; Steurer W. et al., J Immunol.1995, 155(3): 1165-74; Idusogie E E. et al., J Immunol. 2001, 166(4):2571-5; Lazar G A. et al., PNAS, 2006, 103(11): 4005-4010; Ryan M C. etal., Mol. Cancer Ther., 2007, 6: 3009-3018; Richards J O., et al., MolCancer Ther. 2008, 7(8): 2517-27; Shields R. L. et al, J. Biol. Chem,2002, 277: 26733-26740; Shinkawa T. et al, J. Biol. Chem, 2003, 278:3466-3473.

CDC activity of the antibodies provided herein can also be altered, forexample, by improving or diminishing C1q binding and/or CDC (see, forexample, WO99/51642; Duncan & Winter Nature 322:738-40 (1988); U.S. Pat.Nos. 5,648,260; 5,624,821); and WO94/29351 concerning other examples ofFc region variants. One or more amino acids selected from amino acidresidues 329, 331 and 322 of the Fc region can be replaced with adifferent amino acid residue to alter C1q binding and/or reduced orabolished complement dependent cytotoxicity (CDC) (see, U.S. Pat. No.6,194,551 by Idusogie et al). One or more amino acid substitution(s) canalso be introduced to alter the ability of the antibody to fixcomplement (see PCT Publication WO 94/29351 by Bodmer et al.).

The term “Antibody-dependent cellular phagocytosis” and “ADCP” refer toa process by which antibody-coated cells or particles are internalized,either in whole or in part, by phagocytic immune cells (e.g.,macrophages, neutrophils and dendritic cells) that bind to animmunoglobulin Fc region. Methods for altering the ADCP activity ofantibodies by antibody engineering are known in the art, see forexample, Kellner C et al., Transfus Med Hemother, (2017)44:327-336 andChung A W et al., AIDS, (2014) 28:2523-2530.

Examples of Fc variants are known in the art, see, for example, Wang etal., Protein Cell 2018, 9(1): 63-73 and Kang et al., Exp & Mol., Med.(2019) 51:138, which are incorporated herein to their entirety.

i) Fc Variant with Enhanced Effector Functions

In certain embodiments, the Fc variants provided herein has increasedADCC and/or increased affinity to an Fcγ receptor (e.g. FcγRI (CD64),FcγRII (CD32) and/or FcγRIII (CD16)) relative to a wildtype Fc (e.g. Fcof IgG1). In certain embodiments, an Fc variant comprises one or moreamino acid substitution(s) at one or more of the following positions:234, 235, 236, 238, 239, 240, 241, 243, 244, 245, 246, 247, 248, 249,252, 254, 255, 256, 258, 260, 262, 263, 264, 265, 267, 268, 269, 270,272, 274, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294, 295,296, 298, 299, 300, 301, 303, 304, 305, 307, 309, 312, 313, 315, 320,322, 324, 325, 326, 327, 329, 330, 331, 332, 333, 334, 335, 337, 338,339, 340, 345, 360, 373, 376, 378, 382, 388, 389, 396, 398, 414, 416,419, 430, 433, 434, 435, 436, 437, 438, 439 and 440 of the Fc region(see WO 00/42072 by Presta, WO2006/019447 by Lazar, and WO2016/196228,incorporated herein to its entirety), wherein the numbering of theresidues in the Fc region is that of the EU index as in Kabat (see,Kabat E. A. et al., Sequences of Proteins of immunological Interest, 5thEd. Public Health Service, National Institutes of Health, Bethesda, Md.(1991)). Exemplary substitutions for increased effector functionsinclude, without limitation, 234Y, 235Q, 236A, 236W, 239D, 239E, 239M,243L, 247I, 268D, 267E, 268D, 268E, 268F, 270E, 280H, 290S, 292P, 298A,298D, 298V, 300L, 305I, 324T, 326A, 326D, 326W, 330L, 330M, 333S, 332D,332E, 298A, 333A, 334A, 334E, 326A, 247I, 339D, 339Q, 345R, 280H, 290S,298D, 298V, 243L, 292P, 300L, 396L, 305I, 396L, 430G, 440Y, or anycombination thereof (such as 239D/332E, 239D/332E/330L, 236A/332E,236A/239D/332E, 268F/324T, 267E/268F, 267E/324T, and 267E/268F/324T)(see, WO2016/196228; Richards et al. (2008) Mol. Cancer Therap. 7:2517;Moore et al. (2010) mAbs 2:181; and Strohl (2009) Current Opinion inBiotechnology 20:685-691).

Specific mutations at positions 256, 290, 298, 333, 334 and 339 wereshown to improve binding to FcγRIII. Additionally, the followingcombination mutants were shown to improve FcγRIII binding: T256A/S298A,S298A/E333A, S298A/K224A, F243L/R292P/Y300L/V305I/P396L,S298A/E333A/K334A and L234Y/L235Q/G236W/S239M/H268D/D270E/S298A in oneheavy chain and D270E/K326D/A330M/K334E in the opposing heavy chain(having enhanced FcγRIII binding and ADCC activity). Other Fc variantswith strongly enhanced binding to FcγRIIIa include variant withS239D/I332E and S239D/I332E/A330L mutations, which showed the greatestincrease in affinity for FcγRIIIa, a decrease in FcγRIIb binding, andstrong cytotoxic activity, and variants with L235V, F243L, R292P, Y300L,V305I and P396L mutations, which exhibited enhancing FcγRIIIa andconcomitantly enhanced ADCC activity. (see Lazar et a. (2006) Proc.Nat'l Acad Sci. (USA) 103:4005; Awan et al. (2010) Blood 115: 1204;Desjarlais & Lazar (2011) Exp. Cell Res, Stavenhagen et al. (2007)Cancer Res 67:8882). Modifications that increase binding to Clq can beintroduced in order to enhance CDC activity. Exemplary modificationsinclude, a K326 (e.g., K326W) and/or E333 modification in an IgG2, or aS267E/H268F/S324T modification, alone or in any combination, in an IgGl(see Idusogie et al. (2001) J. Immunol. 166:2571, Moore et al. (2010)mAbs 2: 181). Other exemplary modifications include, K326W/E333S,S267E/H268F/S324T, and E345R/E430G/S440Y.

ii) Fc with Reduced Effector Functions

In certain embodiments, the Fc variants provided herein has reducedeffector functions relative to a wildtype Fc (e.g. Fc of IgG1), andcomprise one or more amino acid substitution(s) at a position selectedfrom the group consisting of: 220, 226, 229, 233, 234, 235, 236, 237,238, 267, 268, 269, 270, 297, 309, 318, 320, 322, 325, 328, 329, 330,and 331 of the Fc region (see, WO2016/196228; Richards et al. (2008)Mol. Cancer Therap. 7:2517; Moore et al. (2010) mAbs 2:181; and Strohl(2009) Current Opinion in Biotechnology 20:685-691), wherein thenumbering of the residues in the Fc region is that of the EU index as inKabat. Exemplary substitutions for reduced effector functions include,without limitation, 220S, 226S, 228P, 229S, 233P, 234V, 234G, 234A,234F, 234A, 235A, 235G, 235E, 236E, 236R, 237A, 237K, 238S, 267R, 268A,268Q, 269R, 297A, 297Q, 297G, 309L, 318A, 322A, 325L, 328R, 330S, 331S,or any combination thereof (see, WO2016/196228; and Strohl (2009)Current Opinion in Biotechnology 20:685-691).

In certain embodiments, the Fc variant provided herein is of IgG1isotype and comprises one or more amino acid substitution(s) selectedfrom the group consisting of: L234A, L234F, L234V, F234A, V234A, L235A,L235E, G237A, P238S, H268Q, H268A, N297A, N297Q, N297G, V309L, A330S,and P331S, or any combination thereof (such as L234A/L235A). In certainembodiments, the Fc variant provided herein is of IgG2 isotype, andcomprises one or more amino acid substitution(s) selected from the groupconsisting of: H268Q, V309L, A330S, P331S, V234A, G237A, P238S, H268A,and any combination thereof. In certain embodiments, the Fc variantprovided herein is of IgG4 isotype, and comprises one or more amino acidsubstitution(s) selected from the group consisting of: S228P, F234A,L235E, L235A, G237A, E318A, N297A, N297Q, N297G, and any combinationthereof. In certain embodiments, the anti-SARS-COV-2 antibodies andantigen-binding fragments provided herein is of IgG2/IgG4 cross isotype.Examples of IgG2/IgG4 cross isotype is described in Rother R P et al,Nat Biotechnol 25:1256-1264 (2007).

iii) Fc with Altered Binding to FcRn

In certain embodiments, the Fc variant comprises one or more amino acidsubstitution(s) that improves binding affinity to neonatal Fc receptor(FcRn) at pH 6.0 while retaining minimal binding at pH 7.4. Such avariant can have an extended pharmacokinetic half-life, as it binds toFcRn at acidic pH which allows it to escape from degradation in thelysosome and then be translocated and released out of the cell. Methodsof engineering an antibody and antigen-binding fragment thereof toimprove binding affinity with FcRn are well-known in the art, see, forexample, Vaughn, D. et al, Structure, 6(1): 63-73, 1998; Kontermann, R.et al, Antibody Engineering, Volume 1, Chapter 27: Engineering of the Fcregion for improved PK, published by Springer, 2010; Yeung, Y. et al,Cancer Research, 70: 3269-3277 (2010); Hinton, P. et al, J. Immunology,176:346-356 (2006); Petkova et al. (2006) Int. Immunol. 18:1759, BallAcqua et al. Journal of Immunology 2002, 169:5171-5180, Dall'Acqua W F.et al., J Biol Chem. 281:23514-23524 (2006); Zalevsky J, et al, NatBiotechnol.; 28:157-159 (2010); WO 2009/086320; U.S. Pat. Nos.6,277,375; 6,821,505; WO 97/34631; and WO 2002/060919.

Non-limiting examples of Fc modifications that may result in an increasein serum half-life of the antibody when administered include, e.g.,substitution(s) at one or more positions selected from: 234 (e.g., withF), 235 (e.g., with Q), 238 (e.g., with D), 250 (e.g., with E or Q), 252(e.g., with L/Y/F/W or T), 254 (e.g., with S or T), 256 (e.g., withS/R/Q/E/D or T); 259 (e.g., with I); 272 (e.g., with A), 305(e.g., withA), 307(e.g., with A or P), 308 (e.g., with F, C or P), 311 (e.g., withA or R), 312 (e.g., with A), 322 (e.g., Q), 328 (e.g. E), 331 (e.g.,with A), 378 (e.g., with A), 380 (e.g., with A), 382 (e.g., with A), 428(e.g., with L or F), 432 (e.g., with C), 433 (e.g., with H/L/R/S/P/Q orK), 434 (e.g., with H/F or Y or S or A or W), 435 (e.g. with H), 436(e.g., with L) and 437 (e.g., with C) (all positions by EU numbering)(see, WO2016049000A2; WO2020052692; WO2016196228). In some embodiments,the Fc variant comprises one or more amino acid substitution(s) selectedfrom the group consisting of 234F, 235Q, 238D, 250Q, 252T, 252Y, 254T,256E, 259I, 272A, 305A, 307A, 308F, 311A, 322Q, 328E, 331S, 380A, 428L,432C, 433K, 433S, 434S, 434Y, 434F, 434W, 434A, 435H, 436L, 437C and anycombination thereof. In some embodiments, the Fc modifications comprisesone or pairs or groups of modifications selected from: a) a 428L (e.g.,M428L) and 434S (e.g., N434S) substitution; a 428L, 259I (e.g., V259I),and 308F (e.g., V308F) substitution; b) a 433K (e.g., H433K) and 434(e.g., N434Y or N434F) substitution; c) a 252Y, 254T, and 256E (e.g.,M252Y, S254T, and T256E) substitution; d) a 250Q and 428L substitution(e.g., T250Q and M428L); e) a 307A, 380A and 434A substitution (e.g.,T307A, E380A and N434A); f) a P238D and L328E substitution; g) a L234F,L235Q, K322Q, M252T, S254T and T256E substitution; and h) and a L432C,H433S, N434W, Y436L and T437C substitution.

In some embodiments, hybrid IgG isotypes may be used to increase FcRnbinding and half-life of antibodies. A hybrid Ig can be generated fromtwo or more isotypes. For example, an IgGl/IgG3 hybrid variant may beconstructed by substituting IgGl positions in the CH2 and/or CH3 regionwith the amino acids from IgG3 at positions where the two isotypesdiffer. In some embodiments, a hybrid Ig can comprises one or moremodifications (e.g. substitutions) disclosed here.

Antigen-Binding Fragments

Provided herein are also anti-SARS-CoV-2 antigen-binding fragments. Insome embodiments, the antibodies and antigen-binding fragments providedherein comprise all or a portion of the heavy chain variable domainand/or all or a portion of the light chain variable domain.

Various types of antigen-binding fragments are known in the art and canbe developed based on the anti-SARS-CoV-2 antibodies provided herein,including for example, the exemplary antibodies whose CDR are shown inTables 1 above, and variable sequences are shown in Tables 2 and 3, andtheir different variants (such as affinity variants, glycosylationvariants, Fc variants, cysteine-engineered variants and so on).

In certain embodiments, an anti-SARS-CoV-2 antigen-binding fragmentprovided herein is a diabody, a Fab, a Fab′, a F(ab′)₂, a Fd, an Fvfragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv)₂, abispecific dsFv (dsFv-dsFv′), a disulfide stabilized diabody (dsdiabody), a single-chain antibody molecule (scFv), an scFv dimer(bivalent diabody), a bispecific scFv dimer, a multispecific antibody, aheavy chain antibody, a camelized single domain antibody, a nanobody, adomain antibody, and a bivalent domain antibody.

Various techniques can be used for the production of suchantigen-binding fragments. Illustrative methods include, enzymaticdigestion of intact antibodies (see, e.g. Morimoto et al., Journal ofBiochemical and Biophysical Methods 24:107-117 (1992); and Brennan etal., Science, 229:81 (1985)), recombinant expression by host cells suchas E. coli (e.g. for Fab, Fv and ScFv antibody fragments), screeningfrom a phage display library as discussed above (e.g. for ScFv), andchemical coupling of two Fab′-SH fragments to form F(ab′)₂ fragments(Carter et al., Bio/Technology 10:163-167 (1992)). Other techniques forthe production of antibody fragments will be apparent to a personskilled in the art.

In certain embodiments, the antigen-binding fragment is a scFv.Generation of scFv is described in, for example, WO 93/16185; U.S. Pat.Nos. 5,571,894; and 5,587,458. ScFv may be fused to an effector proteinat either the amino or the carboxyl terminus to provide for a fusionprotein (see, for example, Antibody Engineering, ed. Borrebaeck).

In certain embodiments, the anti-SARS-CoV-2 antibodies orantigen-binding fragments thereof provided herein are bivalent,tetravalent, hexavalent, or multivalent. Any molecule being more thanbivalent is considered multivalent, encompassing for example, trivalent,tetravalent, hexavalent, and so on.

A bivalent molecule can be monospecific if the two binding sites areboth specific for binding to the same antigen or the same epitope. This,in certain embodiments, provides for stronger binding to the antigen orthe epitope than a monovalent counterpart. Similar, a multivalentmolecule may also be monospecific. In certain embodiments, in a bivalentor multivalent antigen-binding moiety, the first valent of binding siteand the second valent of binding site are structurally identical (i.e.having the same sequences), or structurally different (i.e. havingdifferent sequences albeit with the same specificity).

A bivalent can also be bispecific, if the two binding sites are specificfor different or overlapping antigens or epitopes. This also applies toa multivalent molecule. For example, a trivalent molecule can bebispecific when two binding sites are monospecific for a first antigen(or epitope) and the third binding site is specific for a second antigen(or epitope).

Bispecific (or Bivalent) Antibody or Antigen-Binding Fragments

In another aspect, the present disclosure provides bispecific (orbivalent) antibody molecules comprising an anti-SARS-CoV-2 antibody orantigen-binding fragment thereof as disclosed herein. In certainembodiments, the bispecific (or bivalent) antibodies provided hereincomprises a first antigen-binding domain and a second antigen-bindingdomain, wherein the first antigen-binding domains is derived from amonoclonal antibody selected from the group consisting of P2A-1A8,P2A-1A9, P2B-2G11, P2A-1A10, P2A-1B3, P2B-2F6, P2B-2G4, P2C-1A3,P2C-1C8, P2C-1C10, P2C-1D5, P2C-1F11, P2B-1G5, P2B-1A1, P2C-1D7,P2B-1A10, P2B-1D9, P2B-1E4, P2B-1G1, P4A-2D9, P5A-2G7, P5A-3C8, P5A-1D2,P5A-2F11, P5A-2E1, P5A-1C8, P1A-1C10, P4A-1H6, P4B-1F4, P5A-1B6,P5A-1B8, P5A-1B9, P5A-1D1, P5A-1D10, P5A-2D11, P5A-2G9, P5A-2H3,P5A-3A1, P5A-3A6, P5A-3B4, P5A- 3C12, and P22A-1D1. The secondantigen-binding domain can be derived from any suitable antibody.

In certain embodiments, the bispecific (or bivalent) antibodies providedherein comprises a first antigen-binding domain and a secondantigen-binding domain, wherein the first and the second antigen-bindingdomains are derived from any two monoclonal antibodies selected from thegroup consisting of P2A-1A8, P2A-1A9, P2B-2G11, P2A-1A10, P2A-1B3,P2B-2F6, P2B-2G4, P2C-1A3, P2C-1C8, P2C-1C10, P2C-1D5, P2C-1F11,P2B-1G5, P2B- 1A1, P2C-1D7, P2B-1A10, P2B-1D9, P2B-1E4, P2B-1G1,P4A-2D9, P5A-2G7, P5A-3C8, P5A-1D2, P5A-2F11, P5A-2E1, P5A-1C8,P1A-1C10, P4A-1H6, P4B-1F4, P5A-1B6, P5A- 1B8, P5A-1B9, P5A-1D1,P5A-1D10, P5A-2D11, P5A-2G9, P5A-2H3, P5A-3A1, P5A-3A6, P5A-3B4,P5A-3C12, and P22A-1D1. Any two monoclonal antibodies from the above 42antibodies can be combined, as if each and every possible combination oftwo antibodies have been set forth herein individually. In certainembodiments, the bispecific (or bivalent) antibodies provided hereincomprises a first antigen-binding domain and a second antigen-bindingdomain, wherein the first and the second antigen-binding domains arederived from any two monoclonal antibodies selected from the groupconsisting of P2B-2F6, P2C-1F11, P2B-1G5, P2B-1A1, P2C-1D7, P2B-1A10,P2B-1D9, P2B-1E4, P2B-1G1, P4A-2D9, P5A-2G7, P5A-3C8, P5A-1D2, P5A-2F11,P5A-2E1, P5A-1C8, P1A-1C10, P4A-1H6, P4B-1F4, P5A-1B6, P5A-1B8, P5A-1B9,P5A-1D1, P5A-1D10, P5A-2D11, P5A-2G9, P5A-2H3, P5A- 3A1, P5A-3A6,P5A-3B4, P5A-3C12, and P22A-1D1. Any two monoclonal antibodies from theabove 32 antibodies can be combined, as if each and every possiblecombination of two antibodies have been set forth herein individually.

In certain embodiments, the first and the second antigen-binding domainsare derived from P2C-1F11 and P2B-2F6, respectively. In certainembodiments, the first and the second antigen-binding domains arederived from P2C-1F11 and P2A-1A8, respectively. In certain embodiments,the first and the second antigen-binding domains are derived fromP2C-1F11 and P2A-1A9, respectively. In certain embodiments, the firstand the second antigen-binding domains are derived from P2C-1F11 andP2B-2G11, respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2C-1F11 and P2A-1A10,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2C-1F11 and P2A-1B3,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2C-1F11 and P2B-2G4,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2C-1F11 and P2C-1A3,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2C-1F11 and P2C-1C8,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2C-1F11 and P2C-1C10,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2C-1F11 and P2C-1D5,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2C-1F11 and P2C-1F11,respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived from P2A-1A8 and P2A-1A9, respectively. In certainembodiments, the first and the second antigen-binding domains arederived from P2A-1A8 and P2B-2G11, respectively. In certain embodiments,the first and the second antigen-binding domains are derived fromP2A-1A8 and P2A-1A10, respectively. In certain embodiments, the firstand the second antigen-binding domains are derived from P2A-1A8 andP2A-1B3, respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2A-1A8 and P2B-2F6,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2A-1A8 and P2B-2G4,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2A-1A8 and P2C-1A3,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2A-1A8 and P2C-1C8,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2A-1A8 and P2C-1C10,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2A-1A8 and P2C-1D5,respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived from P2A-1A9 and 2B-2G11, respectively. In certainembodiments, the first and the second antigen-binding domains arederived from P2A-1A9 and P2A-1A10, respectively. In certain embodiments,the first and the second antigen-binding domains are derived fromP2A-1A9 and P2A-1B3, respectively. In certain embodiments, the first andthe second antigen-binding domains are derived from P2A-1A9 and P2B-2F6,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2A-1A9 and P2B-2G4,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2A-1A9 and P2C-1A3,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2A-1A9 and P2C-1C8,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2A-1A9 and P2C-1C10,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2A-1A9 and P2C-1D5,respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived from P2B-2G11 and P2A-1A10, respectively. In certainembodiments, the first and the second antigen-binding domains arederived from P2B-2G11 and P2A-1B3, respectively. In certain embodiments,the first and the second antigen-binding domains are derived fromP2B-2G11 and P2B-2F6, respectively. In certain embodiments, the firstand the second antigen-binding domains are derived from P2B-2G11 andP2B-2G4, respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2B-2G11 and P2C-1A3,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2B-2G11 and P2C-1C8,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2B-2G11 and P2C-1C10,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2B-2G11 and P2C-1D5,respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived from P2A-1A10 and P2A-1B3, respectively. In certainembodiments, the first and the second antigen-binding domains arederived from P2A-1A10 and P2B-2F6, respectively. In certain embodiments,the first and the second antigen-binding domains are derived fromP2A-1A10 and P2B-2G4, respectively. In certain embodiments, the firstand the second antigen-binding domains are derived from P2A-1A10 andP2C-1A3, respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2A-1A10 and P2C-1C8,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2A-1A10 and P2C-1C10,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2A-1A10 and P2C-1D5,respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived from P2A-1B3 and P2B-2F6, respectively. In certainembodiments, the first and the second antigen-binding domains arederived from P2A-1B3 and P2B-2G4, respectively. In certain embodiments,the first and the second antigen-binding domains are derived fromP2A-1B3 and P2C-1A3, respectively. In certain embodiments, the first andthe second antigen-binding domains are derived from P2A-1B3 and P2C-1C8,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2A-1B3 and P2C-1C10,respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2A-1B3 and P2C-1D5,respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived from P2B-2F6 and P2B-2G4, respectively. In certainembodiments, the first and the second antigen-binding domains arederived from P2B-2F6 and P2C-1A3, respectively. In certain embodiments,the first and the second antigen-binding domains are derived fromP2B-2F6 and P2C-1C8, respectively. In certain embodiments, the first andthe second antigen-binding domains are derived from P2B-2F6 andP2C-1C10, respectively. In certain embodiments, the first and the secondantigen-binding domains are derived from P2B-2F6 and P2C-1D5,respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived from P2B-2G4 and P2C-1A3, respectively. In certainembodiments, the first and the second antigen-binding domains arederived from P2B-2G4 and P2C-1C8, respectively. In certain embodiments,the first and the second antigen-binding domains are derived fromP2B-2G4 and P2C-1C10, respectively. In certain embodiments, the firstand the second antigen-binding domains are derived from P2B-2G4 andP2C-1D5, respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived from P2C-1A3 and P2C-1C8, respectively. In certainembodiments, the first and the second antigen-binding domains arederived from P2C-1A3 and P2C-1C10, respectively. In certain embodiments,the first and the second antigen-binding domains are derived fromP2C-1A3 and P2C-1D5, respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived from P2C-1C8 and P2C-1C10, respectively. In certainembodiments, the first and the second antigen-binding domains arederived from P2C-1C8 and P2C-1D5, respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived or from P2C-1C10 and P2C-1D5, respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived or from P2C-1F11 and P2B-1G5, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1F11 and P2B-1A1 respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1F11 and P2C-1D7, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1F11 and P2B-1A10, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1F11 and P2B-1D9, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1F11 and P2B-1E4, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1F11 and P2B-1G1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1F11 and P4A-2D9, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1F11 and P5A-2G7, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1F11 and P5A-3C8, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1F11 and P5A-1D2, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1F11 and P5A-2F11, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1F11 and P5A-2E1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1F11 and P5A-1C8, respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived or from P2B-2F6 and P2B-1G5, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-2F6 and P2B-1A1 respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-2F6 and P2C-1D7, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-2F6 and P2B-1A10, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-2F6 and P2B-1D9, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-2F6 and P2B-1E4, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-2F6 and P2B-1G1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-2F6 and P4A-2D9, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-2F6 and P5A-2G7, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-2F6 and P5A-3C8, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-2F6 and P5A-1D2, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-2F6 and P5A-2F11, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-2F6 and P5A-2E1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-2F6 and P5A-1C8, respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived or from P2B-1G5 and P2B-1A1 respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1G5 and P2C-1D7, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1G5 and P2B-1A10, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1G5 and P2B-1D9, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1G5 and P2B-1E4, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1G5 and P2B-1G1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1G5 and P4A-2D9, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1G5 and P5A-2G7, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1G5 and P5A-3C8, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1G5 and P5A-1D2, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1G5 and P5A-2F11, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1G5 and P5A-2E1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1G5 and P5A-1C8, respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived or from P2B-1A1 and P2C-1D7, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1A1 and P2B-1A10, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1A1 and P2B-1D9, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1A1 and P2B-1E4, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1A1 and P2B-1G1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1A1 and P4A-2D9, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1A1 and P5A-2G7, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1A1 and P5A-3C8, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1A1 and P5A-1D2, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1A1 and P5A-2F11, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1A1 and P5A-2E1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1A1 and P5A-1C8, respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived or from P2C-1D7 and P2B-1A10, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1D7 and P2B-1D9, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1D7 and P2B-1E4, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1D7 and P2B-1G1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1D7 and P4A-2D9, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1D7 and P5A-2G7, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1D7 and P5A-3C8, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1D7 and P5A-1D2, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1D7 and P5A-2F11, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1D7 and P5A-2E1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2C-1D7 and P5A-1C8, respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived or from P2B-1A10 and P2B-1D9, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1A10 and P2B-1E4, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1A10 and P2B-1G1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1A10 and P4A-2D9, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1A10 and P5A-2G7, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1A10 and P5A-3C8, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1A10 and P5A-1D2, respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived or from P2B-1A10 and P5A-2F11, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1A10 and P5A-2E1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1A10 and P5A-1C8, respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived or from P2B-1D9 and P2B-1E4, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1D9 and P2B-1G1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1D9 and P4A-2D9, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1D9 and P5A-2G7, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1D9 and P5A-3C8, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1D9 and P5A-1D2, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1D9 and P5A-2F 11, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1D9 and P5A-2E1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1D9 and P5A-1C8, respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived or from P2B-1E4 and P2B-1G1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1E4 and P4A-2D9, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1E4 and P5A-2G7, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1E4 and P5A-3C8, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1E4 and P5A-1D2, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1E4 and P5A-2F11, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1E4 and P5A-2E1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1E4 and P5A-1C8, respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived or from P2B-1G1 and P4A-2D9, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1G1 and P5A-2G7, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1G1 and P5A-3C8, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1G1 and P5A-1D2, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1G1 and P5A-2F11, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1G1 and P5A-2E1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P2B-1G1 and P5A-1C8, respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived or from P4A-2D9 and P5A-2G7, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P4A-2D9 and P5A-3C8, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P4A-2D9 and P5A-1D2, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P4A-2D9 and P5A-2F11, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P4A-2D9 and P5A-2E1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P4A-2D9 and P5A-1C8, respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived or from P5A-2G7 and P5A-3C8, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P5A-2G7 and P5A-1D2, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P5A-2G7 and P5A-2F11, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P5A-2G7 and P5A-2E1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P5A-2G7 and P5A-1C8, respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived or from P5A-3C8 and P5A-1D2, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P5A-3C8 and P5A-2F11, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P5A-3C8 and P5A-2E1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P5A-3C8 and P5A-1C8, respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived or from P5A-1D2 and P5A-2F11, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P5A-1D2 and P5A-2E1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P5A-1D2 and P5A-1C8, respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived or from P5A-2F11 and P5A-2E1, respectively. In certainembodiments, the first and the second antigen-binding domains arederived or from P5A-2F11 and P5A-1C8, respectively.

In certain embodiments, the first and the second antigen-binding domainsare derived or from P5A-2E1 and P5A-1C8, respectively.

In certain embodiments, the bispecific antibody molecules can have atleast two distinct antigen-binding sites with different specificities.In certain embodiments, the bispecific antibody molecules providedherein are capable of binding to different epitopes on the spike proteinof SARS-CoV-2 virus. In some embodiments, the bispecific antibodymolecules provided herein comprises antigen-binding fragments derivedfrom two or more antibodies provided herein. In some embodiments, thetwo or more antibodies bind to different epitopes in RBD of spikeprotein of SARS-CoV-2. In some embodiments, the two or more antibodiesare no more than 70% (or no more than 60%, or no more than 50%)competitive against each other in binding to RBD of spike protein ofSARS-CoV-2 virus. In certain embodiments, the bispecific antibodycomprises a first antigen-binding domain derived from P2C-1F11 and asecond antigen-binding domain derived from an antibody selected from thegroup consisting of P2C-1A3, P2C-1C10, P2B-2F6, P2B-1G5, and P2A-1B3. Incertain embodiments, the bispecific antibody comprises a firstantigen-binding domain derived from P2C-1A3 and a second antigen-bindingdomain derived from an antibody selected from the group consisting ofP2C-1F11, and P2A-1B3. In certain embodiments, the bispecific antibodycomprises a first antigen-binding domain derived from P2B-2F6 and asecond antigen-binding domain derived from an antibody selected from thegroup consisting of P2C-1C10, P2C-1F11, P2B-1G5, and P2A-1B3. In certainembodiments, the bispecific antibody comprises a first antigen-bindingdomain derived from P2A-1B3 and a second antigen-binding domain derivedfrom an antibody selected from the group consisting of P2C-1A3,P2C-1C10, P2C-1F11, P2B-2F6, and P2A-1A10. In some embodiments, the twoor more antibodies comprise a first antibody which comprises P2C-1C10 oran antigen binding fragment thereof, and a second antibody selected fromthe group consisting of P2C-1A3, P2C-1F11, and P2A-1B3, or an antigenbinding fragment thereof.

The term “derived from” as used herein with respect to antigen-bindingdomain, means that the antigen-binding domain comprise at least oneheavy chain CDR sequence (e.g.

comprising heavy chain CDR3, or three heavy chain CDRs) or at least onelight chain CDR sequence (e.g. comprising light chain CDR3, or threeheavy chain CDRs) of the specified monoclonal antibody. In certainembodiments, the first and the second antigen-binding domains comprisesthe heavy chain CDR sequences of the specified monoclonal antibodies,and/or the light chain CDR sequences of the specified monoclonalantibodies. In certain embodiments, the first and the secondantigen-binding domains comprises the heavy chain variable regionsequences of the specified monoclonal antibodies, and/or the light chainvariable region sequences of the specified monoclonal antibodies. Allthe CDR sequences and variable region sequences of the specificmonoclonal antibodies are provided in Tables 1 and 2 of the presentdisclosure.

In certain embodiments, the bispecific antibody molecules providedherein has a first antigen-binding domains specificity directed to theRBD of the spike protein of SARS-CoV-2 virus and a secondantigen-binding domains specificity directed to a second antigen. Incertain embodiments, the second antigen can be for example, an epitopeoutside of RBD on the spike protein of SARS-CoV-2, S2 protein (i.e.which is cleaved from the spike protein), nucleocapsid protein ofSARS-CoV-2, or alternatively the second antigen can be an antigen onhuman immune cells such as T cell, macrophage cell, natural killercells, or antigen-presenting cells.

In certain embodiments, the bispecific antibody molecules as providedherein are based on the format of a “whole” antibody, such as whole IgGor IgG-like molecules. Examples of such bispecific antibody include butare not limited to, those produced by a quadroma cell line. In anotherembodiment, a bispecific IgG-like molecule can be an appended IgG, whichis engineered by appending either the amino or carboxyl termini ofeither light or heavy chains of an IgG of a first specificity withadditional antigen-binding units of a second specificity. The appendedantigen-binding units can be, for example, single domain antibodies(e.g. unpaired VL or VH, or VHH (i.e. heavy chain variable domain of aheavy chain antibody)), paired antibody variable domains (e.g. Fv orscFv) or engineered protein scaffolds. Examples of appended IgG include,without limitation, Double-variable domain (DVD)-Ig, which has a secondheavy chain variable domain (VH) fused to the VH of a first heavy chainand a second variable light chain domain (VL) fused to a first lightchain of the IgG. A DVD-Ig can be bispecific when the first VH/VL andthe second VH/VL are selected to bind to two different antigens. Incertain embodiments, a bispecific IgG or IgG-like molecules can bemonovalent for each antigen and can be produced by co-expression of thetwo light and two heavy chains in a single host cell.

In certain embodiments, the bispecific antibody molecules as providedherein can be small recombinant bispecific formats based on variabledomains, such as single domain antibody, Fv, and Fab, which may lacksome or all of the antibody constant domains. Examples of smallrecombinant bispecific formats include, without limitation, tandemsingle chain variable fragment molecules (taFvs), diabodies (Dbs),single chain diabodies (scDbs) and various other derivatives of these(see, bispecific antibody formats as described by Byrne H. et al. (2013)Trends Biotech, 31 (11): 621-632, BiTE (bispecific T cell engager),DARTs, and TandAb. In certain embodiments, the two antigen-bindingmoieties can be linked by a peptide linker.

In certain embodiments, the bispecific antibody molecules as providedherein are in a bispecific format selected from bispecific IgG-likeantibodies (BsIgG) comprising CrossMab; DAF (two-in-one); DAF(four-in-one); DutaMab; DT-IgG; Knobs-in-holes common LC; Knobs-in-holesassembly; Charge pair; Fab-arm exchange; SEEDbody; Triomab; LUZ-Y; Fcab;kappa-lamda-body; and Orthogonal Fab. For detailed description of thebispecific antibody formats please see Spiess C., Zhai Q. and Carter P.J. (2015) Molecular Immunology 67: 95-106, which is incorporated hereinby reference to its entirety.

In certain embodiments, the bispecific antibody molecules as providedherein are in a bispecific format selected from IgG-appended antibodieswith an additional antigen-binding moiety consisting of DVD-IgG;IgG(H)-scFv; scFv-(H)IgG; IgG(L)-scFv; scFV-(L)IgG; IgG(L,H)-Fv;IgG(H)-V; V(H)-IgG; IgG(L)-V; V(L)-IgG; IgG-scFab; 2scFv-IgG; IgG-2scFv;scFv4-Ig; scFv4-Ig; and Zybody (see Id.).

In certain embodiments, the bispecific antibody molecules as providedherein are in a bispecific format selected from WuxiBody (WuXiBiologics, see, WO2019057122A1, incorporated herein to its entirety);Triomabs; hybrid hybridoma (quadroma); Multispecific anticalin platform(Pieris); Diabodies; Single chain diabodies; Tandem single chain Fvfragments; TandAbs, Trispecific Abs (Affimed); Darts (dual affinityretargeting; Macrogenics); Bispecific Xmabs (Xencor); Bispecific T cellengagers (Bites; Amgen; 55 kDa); Triplebodies; Tribody (Fab-scFv);Fusion Protein (CreativeBiolabs); multifunctional recombinant antibodyderivates; Duobody platform (Genmab); Dock and lock platform; Knob intohole (KIH) platform; Humanized bispecific IgG antibody (REGN1979)(Regeneron); Mabe bispecific antibodies (F-Star); DVD-Ig (dual variabledomain immunoglobulin) (Abbvie); kappa-lambda bodies; TBTI (tetravalentbispecific tandem Ig); and CrossMab.

In certain embodiments, the bispecific antibody molecules as providedherein are in a format selected from bispecific antibody fragmentscomprising Nanobody; Nanobody-HAS; BiTE; Diabody; DART; TandAb;scDiabody; sc-Diabody-CH3; Diabody-CH3; Triple Body; Miniantibody;Minibody; TriBi minibody; scFv-CH3 KIH; Fab-scFv; scFv-CH-CL-scFv;F(ab′)2; F(ab′)2-scFv2; scFv-KIH; Fab-scFv-Fc; Tetravalent HCAb;scDiabody-Fc; Diabody-Fc; Tandem scFv-Fc; and Intrabody (see Id.).

In certain embodiments, the bispecific antibody molecules as providedherein are in a bispecific format such as Dock and Lock; ImmTAC;HSAbody; scDiabody-HAS; and Tandem scFv-Toxin (see Id.).

In certain embodiments, the bispecific antibody molecules as providedherein are based on a format selected from bispecific antibodyconjugates comprising IgG-IgG; Cov-X-Body; and scFv1-PEG-scFv2 (seeId.).

The bispecific antibody molecules provided herein can be made with anysuitable methods known in the art. In a conventional approach, twoimmunoglobulin heavy chain-light chain pairs having differentantigen-binding specificities can be co-expressed in a host cell toproduce bispecific antibodies in a recombinant way (see, for example,Milstein and Cuello, Nature, 305: 537 (1983)), followed by purificationby affinity chromatography.

Recombinant approach may also be used, where sequences encoding theantibody heavy chain variable domains for the two specificities arerespectively fused to immunoglobulin constant domain sequences, followedby insertion to an expression vector which is co-transfected with anexpression vector for the light chain sequences to a suitable host cellfor recombinant expression of the bispecific antibody (see, for example,WO 94/04690; Suresh et al., Methods in Enzymology, 121:210 (1986)).Similarly, scFv dimers can also be recombinantly constructed andexpressed from a host cell (see, e.g. Gruber et al., J. Immunol.,152:5368 (1994).)

Bispecific antibody molecule may be generated from a bispecificantibody, for example, by proteolytic cleavage, or by chemical linking.For example, an antigen-binding fragment (e.g. Fab′) of an antibody maybe prepared and converted to Fab′-thiol derivative and then mixed andreacted with another converted Fab′ derivative having a differentantigenic specificity to form a bispecific antibody molecule (see, forexample, Brennan et al., Science, 229: 81 (1985)).

In certain embodiments, the bispecific antibody molecules may beengineered to promote heavy chain heterodimerization of the twodifferent antigen-binding sites. In certain embodiments, the Fc regionis modified at the interface so that a knob-into-hole association can beformed to promote heterodimerization. “Knob-into-hole” as used herein,refers to an interaction between two polypeptides (such as CH3 domain),where one polypeptide has a protuberance (i.e. “knob”) due to presenceof an amino acid residue having a bulky side chain (e.g. tyrosine ortryptophan), and the other polypeptide has a cavity (i.e. “hole”) wherea small side chain amino acid residue resides (e.g. alanine orthreonine), and the protuberance is positionable in the cavity so as topromote interaction of the two polypeptides to form a heterodimer or acomplex. Methods of generating polypeptides with knobs-into-holes areknown in the art, e.g., as described in U.S. Pat. No. 5,731,168.

In some embodiments, “charged pairs” can be introduced to the Fcpolypeptides to electrostatically steer the formation towardsheterodimerization. Exemplary pairs include, D221E/P228E/L368E pairedwith D221R/P228R/K409R and C220E/P228E/368E paired withC220R/E224R/P228R/K409R (see Gunasekaran et al., 2010, J. Biol. Chem.285(25):19637.).

In some embodiments, the binding interface of the two Fc polypeptidechains can be engineered such that in the heterodimer configuration,residues interact with residues of similar physical property (e.g.,polar residues interacting with polar residues, or hydrophobic residuesinteract with hydrophobic residues), while in the homodimerconfiguration residues interact with residues of different physicalproperty. Exemplary modifications include substitution at positions 364,368, 399, 405, 409, 411, or any combination thereof (see, e.g,WO2014/145806, WO2014/110601, WO2016/086186, WO2016/086189,WO2016/086196, and WO2016/182751).

In some embodiments, the bispecific antibody molecules may be engineeredto reduce random pairing of two different light chain variable regionswith the two different heavy chain variable regions. In someembodiments, the bispecific antibody molecule comprise a common lightchain capable of pairing with the two heavy chain variable regions. Insome other embodiments, CH1 domain of one heavy chain is exchanged withthe constant region (CL) of the corresponding light chain (such as thatapplied in CrossMab technology). In some other embodiments, mutationsare introduced into the CH1-CL interface and/or the VH-VL interface ofthe Fab fragments, so as to enforce correct pairing of the light chainswith the corresponding heavy chains. In some other embodiments, the CH1domain and CL domain in one antigen-binding domain are replaced by TCRconstant domains, so as to minimize mispairing between heavy chain ofthe first antigen-binding domain and light chain of the secondantigen-binding domain (such as that applied in WuxiBody technology).

In some embodiments, the modified antibody or an antigen-bindingfragment thereof of this disclosure, wherein the antigen-binding domaincan comprise:

-   -   a. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        1, SEQ ID NO: 2, and SEQ ID NO: 3;    -   b. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        11, SEQ ID NO: 12, and SEQ ID NO: 13;    -   c. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        21, SEQ ID NO: 22, and SEQ ID NO: 23;    -   d. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        31, SEQ ID NO: 32, and SEQ ID NO: 33;    -   e. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        41, SEQ ID NO: 42, and SEQ ID NO: 43;    -   f. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        51, SEQ ID NO: 52, and SEQ ID NO: 53;    -   g. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        65, SEQ ID NO: 66, and SEQ ID NO: 67;    -   h. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        75, SEQ ID NO: 76, and SEQ ID NO: 77;    -   i. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        85, SEQ ID NO: 86, and SEQ ID NO: 87;    -   j. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        95, SEQ ID NO: 96, and SEQ ID NO: 97;    -   k. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        105, SEQ ID NO: 106, and SEQ ID NO: 107;    -   l. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        136, SEQ ID NO: 137, and SEQ ID NO: 138;    -   m. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        146, SEQ ID NO: 147, and SEQ ID NO: 148;    -   n. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        156, SEQ ID NO: 157, and SEQ ID NO: 158;    -   o. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        166, SEQ ID NO: 167, and SEQ ID NO: 168;    -   p. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        176, SEQ ID NO: 177, and SEQ ID NO: 178;    -   q. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        186, SEQ ID NO: 187, and SEQ ID NO: 188;    -   r. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        196, SEQ ID NO: 197, and SEQ ID NO: 198;    -   s. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        206, SEQ ID NO: 207, and SEQ ID NO: 208;    -   t. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        216, SEQ ID NO: 217, and SEQ ID NO: 218;    -   u. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        226, SEQ ID NO: 227, and SEQ ID NO: 228;    -   v. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        236, SEQ ID NO: 237, and SEQ ID NO: 238;    -   w. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        246, SEQ ID NO: 247, and SEQ ID NO: 248;    -   x. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        256, SEQ ID NO: 257, and SEQ ID NO: 258;    -   y. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        266, SEQ ID NO: 267, and SEQ ID NO: 268;    -   z. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        276, SEQ ID NO: 277, and SEQ ID NO: 278;    -   aa. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 286, SEQ ID NO: 287, and SEQ ID NO: 288;    -   bb. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 296, SEQ ID NO: 297, and SEQ ID NO: 298;    -   cc. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 306, SEQ ID NO: 307, and SEQ ID NO: 308;    -   dd. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 316, SEQ ID NO: 317, and SEQ ID NO: 318;    -   ee. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 326, SEQ ID NO: 327, and SEQ ID NO: 328;    -   . 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        336, SEQ ID NO: 337, and SEQ ID NO: 338;    -   gg. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 346, SEQ ID NO: 347, and SEQ ID NO: 348;    -   hh. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 356, SEQ ID NO: 357, and SEQ ID NO: 358;    -   ii. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 366, SEQ ID NO: 367, and SEQ ID NO: 368;    -   jj. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 376, SEQ ID NO: 377, and SEQ ID NO: 378;    -   kk. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 386, SEQ ID NO: 387, and SEQ ID NO: 388;    -   ll. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 396, SEQ ID NO: 397, and SEQ ID NO: 398;    -   mm. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408;    -   nn. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 416, SEQ ID NO: 417, and SEQ ID NO: 418;    -   oo. 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 426, SEQ ID NO: 427, and SEQ ID NO: 428; or

a combination thereof.

In some embodiments, the modified antibody or antigen binding fragmentdisclosed above, wherein the antigen-binding domain comprises:

-   -   a. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        4, SEQ ID NO: 5, and SEQ ID NO: 6;    -   b. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        14, SEQ ID NO: 15, and SEQ ID NO: 16;    -   c. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        24, SEQ ID NO: 25 and SEQ ID NO: 26;    -   d. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        34, SEQ ID NO: 35 and SEQ ID NO: 36;    -   e. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        44, SEQ ID NO: 45 and SEQ ID NO: 46;    -   f. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        54, SEQ ID NO: 55 and SEQ ID NO: 56;    -   g. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        68, SEQ ID NO: 69, and SEQ ID NO: 70;    -   h. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        78, SEQ ID NO: 79, and SEQ ID NO: 80;    -   i. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        88, SEQ ID NO: 89, and SEQ ID NO: 90.    -   j. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        98, SEQ ID NO: 99, and SEQ ID NO: 100;    -   k. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        108, SEQ ID NO: 109, and SEQ ID NO: 110;    -   l. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        139, SEQ ID NO: 140, and SEQ ID NO: 141;    -   m. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        149, SEQ ID NO: 150, and SEQ ID NO: 151;    -   n. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        159, SEQ ID NO: 160, and SEQ ID NO: 161;    -   o. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        169, SEQ ID NO: 170, and SEQ ID NO: 171;    -   p. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        179, SEQ ID NO: 180, and SEQ ID NO: 181;    -   q. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        189, SEQ ID NO: 190, and SEQ ID NO: 191;    -   r. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        199, SEQ ID NO: 200, and SEQ ID NO: 201;    -   s. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        209, SEQ ID NO: 210, and SEQ ID NO: 211;    -   t. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        219, SEQ ID NO: 220, and SEQ ID NO: 221;    -   u. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        229, SEQ ID NO: 230, and SEQ ID NO: 231;    -   v. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        239, SEQ ID NO: 240, and SEQ ID NO: 241;    -   w. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        249, SEQ ID NO: 250, and SEQ ID NO: 251;    -   x. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        259, SEQ ID NO: 260, and SEQ ID NO: 261;    -   y. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        269, SEQ ID NO: 270, and SEQ ID NO: 271;    -   z. 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        279, SEQ ID NO: 280, and SEQ ID NO: 281;    -   aa. 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 289, SEQ ID NO: 290, and SEQ ID NO: 291;    -   bb. 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 299, SEQ ID NO: 300, and SEQ ID NO: 301;    -   cc. 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 309, SEQ ID NO: 310, and SEQ ID NO: 311;    -   dd. 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 319, SEQ ID NO: 320, and SEQ ID NO: 321;    -   ee. 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 329, SEQ ID NO: 330, and SEQ ID NO: 331;    -   ff. 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 339, SEQ ID NO: 340, and SEQ ID NO: 341;    -   gg. 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 349, SEQ ID NO: 350, and SEQ ID NO: 351;    -   hh. 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 359, SEQ ID NO: 360, and SEQ ID NO: 361;    -   ii. 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 369, SEQ ID NO: 370, and SEQ ID NO: 371;    -   jj. 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 379, SEQ ID NO: 380, and SEQ ID NO: 381;    -   kk. 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 389, SEQ ID NO: 390, and SEQ ID NO: 391;    -   ll. 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 399, SEQ ID NO: 400, and SEQ ID NO: 401;    -   mm. 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 409, SEQ ID NO: 410, and SEQ ID NO: 411;    -   nn. 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 419, SEQ ID NO: 420, and SEQ ID NO: 421;    -   oo. 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 429, SEQ ID NO: 430, and SEQ ID NO: 431; or

a combination thereof.

In some embodiments, the modified antibody or an antigen-bindingfragment thereof disclosed herein, wherein the antigen-binding domaincan comprise:

-   -   a. a heavy chain CDR1 (HCDR1) comprising the sequence of SEQ ID        NO: 1, a heavy chain CDR2 (HCDR2) comprising the sequence of SEQ        ID NO: 2, a heavy chain CDR3 (HCDR3) comprising the sequence of        SEQ ID NO: 3; a light chain CDR1 (LCDR1) comprising the sequence        of SEQ ID NO: 4, a light chain CDR2 (LCDR2) comprising the        sequence of SEQ ID NO: 5, and a light chain CDR3 (LCDR3)        comprising the sequence of SEQ ID NO: 6;    -   b. a HCDR1 comprising the sequence of SEQ ID NO: 11, a HCDR2        comprising the sequence of SEQ ID NO: 12, a HCDR3 comprising the        sequence of SEQ ID NO: 13, a LCDR1 comprising the sequence of        SEQ ID NO: 14, a LCDR2 comprising the sequence of SEQ ID NO: 15,        and a LCDR3 comprising the sequence of SEQ ID NO: 16;    -   c. a HCDR1 comprising the sequence of SEQ ID NO: 21, a HCDR2        comprising the sequence of SEQ ID NO: 22, a HCDR3 comprising the        sequence of SEQ ID NO: 23, a LCDR1 comprising the sequence of        SEQ ID NO: 24, a LCDR2 comprising the sequence of SEQ ID NO: 25,        and a LCDR3 comprising the sequence of SEQ ID NO: 26;    -   d. a HCDR1 comprising the sequence of SEQ ID NO: 31, a HCDR2        comprising the sequence of SEQ ID NO: 32, a HCDR3 comprising the        sequence of SEQ ID NO: 33, a LCDR1 comprising the sequence of        SEQ ID NO: 34, a LCDR2 comprising the sequence of SEQ ID NO: 35,        and a LCDR3 comprising the sequence of SEQ ID NO: 36;    -   e. a HCDR1 comprising the sequence of SEQ ID NO: 41, a HCDR2        comprising the sequence of SEQ ID NO: 42, a HCDR3 comprising the        sequence of SEQ ID NO: 43, a LCDR1 comprising the sequence of        SEQ ID NO: 44, a LCDR2 comprising the sequence of SEQ ID NO: 45,        and a LCDR3 comprising the sequence of SEQ ID NO: 46;    -   f. a HCDR1 comprising the sequence of SEQ ID NO: 51, a HCDR2        comprising the sequence of SEQ ID NO: 52, a HCDR3 comprising the        sequence of SEQ ID NO: 53, a LCDR1 comprising the sequence of        SEQ ID NO: 54, a LCDR2 comprising the sequence of SEQ ID NO: 55,        and a LCDR3 comprising the sequence of SEQ ID NO: 56;    -   g. a HCDR1 comprising the sequence of SEQ ID NO: 65, a HCDR2        comprising the sequence of SEQ ID NO: 66, a HCDR3 comprising the        sequence of SEQ ID NO: 67, a LCDR1 comprising the sequence of        SEQ ID NO: 68, a LCDR2 comprising the sequence of SEQ ID NO: 69,        and a LCDR3 comprising the sequence of SEQ ID NO: 70;    -   h. a HCDR1 comprising the sequence of SEQ ID NO: 75, a HCDR2        comprising the sequence of SEQ ID NO: 76, a HCDR3 comprising the        sequence of SEQ ID NO: 77, a LCDR1 comprising the sequence of        SEQ ID NO: 78, a LCDR2 comprising the sequence of SEQ ID NO: 79,        and a LCDR3 comprising the sequence of SEQ ID NO: 80;    -   i. a HCDR1 comprising the sequence of SEQ ID NO: 85, a HCDR2        comprising the sequence of SEQ ID NO: 86, a HCDR3 comprising the        sequence of SEQ ID NO: 87, a LCDR1 comprising the sequence of        SEQ ID NO: 88, a LCDR2 comprising the sequence of SEQ ID NO: 89,        and a LCDR3 comprising the sequence of SEQ ID NO: 90;    -   j. a HCDR1 comprising the sequence of SEQ ID NO: 95, a HCDR2        comprising the sequence of SEQ ID NO: 96, a HCDR3 comprising the        sequence of SEQ ID NO: 97, a LCDR1 comprising the sequence of        SEQ ID NO: 98, a LCDR2 comprising the sequence of SEQ ID NO: 99,        and a LCDR3 comprising the sequence of SEQ ID NO: 100;    -   k. a HCDR1 comprising the sequence of SEQ ID NO: 105, a HCDR2        comprising the sequence of SEQ ID NO: 106, a HCDR3 comprising        the sequence of SEQ ID NO: 107, a LCDR1 comprising the sequence        of SEQ ID NO: 108, a LCDR2 comprising the sequence of SEQ ID NO:        109, and a LCDR3 comprising the sequence of SEQ ID NO: 110;    -   l. a HCDR1 comprising the sequence of SEQ ID NO: 136, a HCDR2        comprising the sequence of SEQ ID NO: 137, a HCDR3 comprising        the sequence of SEQ ID NO: 138, a LCDR1 comprising the sequence        of SEQ ID NO: 139, a LCDR2 comprising the sequence of SEQ ID NO:        140, and a LCDR3 comprising the sequence of SEQ ID NO: 141;    -   m. HCDR1 comprising the sequence of SEQ ID NO: 146, a HCDR2        comprising the sequence of SEQ ID NO: 147, a HCDR3 comprising        the sequence of SEQ ID NO: 148, a LCDR1 comprising the sequence        of SEQ ID NO: 149, a LCDR2 comprising the sequence of SEQ ID NO:        150, and a LCDR3 comprising the sequence of SEQ ID NO: 151;    -   n. HCDR1 comprising the sequence of SEQ ID NO: 156, a HCDR2        comprising the sequence of SEQ ID NO: 157, a HCDR3 comprising        the sequence of SEQ ID NO: 158, a LCDR1 comprising the sequence        of SEQ ID NO: 159, a LCDR2 comprising the sequence of SEQ ID NO:        160, and a LCDR3 comprising the sequence of SEQ ID NO: 161;    -   o. HCDR1 comprising the sequence of SEQ ID NO: 166, a HCDR2        comprising the sequence of SEQ ID NO: 167, a HCDR3 comprising        the sequence of SEQ ID NO: 168, a LCDR1 comprising the sequence        of SEQ ID NO: 169, a LCDR2 comprising the sequence of SEQ ID NO:        170, and a LCDR3 comprising the sequence of SEQ ID NO: 171;    -   p. HCDR1 comprising the sequence of SEQ ID NO: 176, a HCDR2        comprising the sequence of SEQ ID NO: 177, a HCDR3 comprising        the sequence of SEQ ID NO: 178, a LCDR1 comprising the sequence        of SEQ ID NO: 179, a LCDR2 comprising the sequence of SEQ ID NO:        180, and a LCDR3 comprising the sequence of SEQ ID NO: 181;    -   q. HCDR1 comprising the sequence of SEQ ID NO: 186, a HCDR2        comprising the sequence of SEQ ID NO: 187, a HCDR3 comprising        the sequence of SEQ ID NO: 188, a LCDR1 comprising the sequence        of SEQ ID NO: 189, a LCDR2 comprising the sequence of SEQ ID NO:        190, and a LCDR3 comprising the sequence of SEQ ID NO: 191;    -   r. HCDR1 comprising the sequence of SEQ ID NO: 196, a HCDR2        comprising the sequence of SEQ ID NO: 197, a HCDR3 comprising        the sequence of SEQ ID NO: 198, a LCDR1 comprising the sequence        of SEQ ID NO: 199, a LCDR2 comprising the sequence of SEQ ID NO:        200, and a LCDR3 comprising the sequence of SEQ ID NO: 201;    -   s. HCDR1 comprising the sequence of SEQ ID NO: 206, a HCDR2        comprising the sequence of SEQ ID NO: 207, a HCDR3 comprising        the sequence of SEQ ID NO: 208, a LCDR1 comprising the sequence        of SEQ ID NO: 209, a LCDR2 comprising the sequence of SEQ ID NO:        210, and a LCDR3 comprising the sequence of SEQ ID NO: 211;    -   t. HCDR1 comprising the sequence of SEQ ID NO: 216, a HCDR2        comprising the sequence of SEQ ID NO: 217, a HCDR3 comprising        the sequence of SEQ ID NO: 218, a LCDR1 comprising the sequence        of SEQ ID NO: 219, a LCDR2 comprising the sequence of SEQ ID NO:        220, and a LCDR3 comprising the sequence of SEQ ID NO: 221;    -   u. HCDR1 comprising the sequence of SEQ ID NO: 226, a HCDR2        comprising the sequence of SEQ ID NO: 227, a HCDR3 comprising        the sequence of SEQ ID NO: 228, a LCDR1 comprising the sequence        of SEQ ID NO: 229, a LCDR2 comprising the sequence of SEQ ID NO:        230, and a LCDR3 comprising the sequence of SEQ ID NO: 231;    -   v. HCDR1 comprising the sequence of SEQ ID NO: 236, a HCDR2        comprising the sequence of SEQ ID NO: 237, a HCDR3 comprising        the sequence of SEQ ID NO: 238, a LCDR1 comprising the sequence        of SEQ ID NO: 239, a LCDR2 comprising the sequence of SEQ ID NO:        240, and a LCDR3 comprising the sequence of SEQ ID NO: 241;    -   w. HCDR1 comprising the sequence of SEQ ID NO: 246, a HCDR2        comprising the sequence of SEQ ID NO: 247, a HCDR3 comprising        the sequence of SEQ ID NO: 248, a LCDR1 comprising the sequence        of SEQ ID NO: 249, a LCDR2 comprising the sequence of SEQ ID NO:        250, and a LCDR3 comprising the sequence of SEQ ID NO: 251;    -   x. HCDR1 comprising the sequence of SEQ ID NO: 256, a HCDR2        comprising the sequence of SEQ ID NO: 257, a HCDR3 comprising        the sequence of SEQ ID NO: 258, a LCDR1 comprising the sequence        of SEQ ID NO: 259, a LCDR2 comprising the sequence of SEQ ID NO:        260, and a LCDR3 comprising the sequence of SEQ ID NO: 261;    -   y. HCDR1 comprising the sequence of SEQ ID NO: 266, a HCDR2        comprising the sequence of SEQ ID NO: 267, a HCDR3 comprising        the sequence of SEQ ID NO: 268, a LCDR1 comprising the sequence        of SEQ ID NO: 269, a LCDR2 comprising the sequence of SEQ ID NO:        270, and a LCDR3 comprising the sequence of SEQ ID NO: 271;    -   z. HCDR1 comprising the sequence of SEQ ID NO: 276, a HCDR2        comprising the sequence of SEQ ID NO: 277, a HCDR3 comprising        the sequence of SEQ ID NO: 278, a LCDR1 comprising the sequence        of SEQ ID NO: 279, a LCDR2 comprising the sequence of SEQ ID NO:        280, a LCDR3 comprising the sequence of SEQ ID NO: 281;    -   aa. HCDR1 comprising the sequence of SEQ ID NO: 286, a HCDR2        comprising the sequence of SEQ ID NO: 287, a HCDR3 comprising        the sequence of SEQ ID NO: 288, a LCDR1 comprising the sequence        of SEQ ID NO: 289, a LCDR2 comprising the sequence of SEQ ID NO:        290, a LCDR3 comprising the sequence of SEQ ID NO: 291;    -   bb. HCDR1 comprising the sequence of SEQ ID NO: 296, a HCDR2        comprising the sequence of SEQ ID NO: 297, a HCDR3 comprising        the sequence of SEQ ID NO: 298, a LCDR1 comprising the sequence        of SEQ ID NO: 299, a LCDR2 comprising the sequence of SEQ ID NO:        300, a LCDR3 comprising the sequence of SEQ ID NO: 301;    -   cc. HCDR1 comprising the sequence of SEQ ID NO: 306, a HCDR2        comprising the sequence of SEQ ID NO: 307, a HCDR3 comprising        the sequence of SEQ ID NO: 308, a LCDR1 comprising the sequence        of SEQ ID NO: 309, a LCDR2 comprising the sequence of SEQ ID NO:        310, a LCDR3 comprising the sequence of SEQ ID NO: 311;    -   dd. HCDR1 comprising the sequence of SEQ ID NO: 316, a HCDR2        comprising the sequence of SEQ ID NO: 317, a HCDR3 comprising        the sequence of SEQ ID NO: 318, a LCDR1 comprising the sequence        of SEQ ID NO: 319, a LCDR2 comprising the sequence of SEQ ID NO:        320, a LCDR3 comprising the sequence of SEQ ID NO: 321;    -   ee. HCDR1 comprising the sequence of SEQ ID NO: 326, a HCDR2        comprising the sequence of SEQ ID NO: 327, a HCDR3 comprising        the sequence of SEQ ID NO: 328, a LCDR1 comprising the sequence        of SEQ ID NO: 329, a LCDR2 comprising the sequence of SEQ ID NO:        330, a LCDR3 comprising the sequence of SEQ ID NO: 331;    -   ff. HCDR1 comprising the sequence of SEQ ID NO: 336, a HCDR2        comprising the sequence of SEQ ID NO: 337, a HCDR3 comprising        the sequence of SEQ ID NO: 338, a LCDR1 comprising the sequence        of SEQ ID NO: 339, a LCDR2 comprising the sequence of SEQ ID NO:        340, a LCDR3 comprising the sequence of SEQ ID NO: 341;    -   gg. HCDR1 comprising the sequence of SEQ ID NO: 346, a HCDR2        comprising the sequence of SEQ ID NO: 347, a HCDR3 comprising        the sequence of SEQ ID NO: 348, a LCDR1 comprising the sequence        of SEQ ID NO: 349, a LCDR2 comprising the sequence of SEQ ID NO:        350, a LCDR3 comprising the sequence of SEQ ID NO: 351;    -   hh. HCDR1 comprising the sequence of SEQ ID NO: 356, a HCDR2        comprising the sequence of SEQ ID NO: 357, a HCDR3 comprising        the sequence of SEQ ID NO: 358, a LCDR1 comprising the sequence        of SEQ ID NO: 359, a LCDR2 comprising the sequence of SEQ ID NO:        360, a LCDR3 comprising the sequence of SEQ ID NO: 361;    -   ii. HCDR1 comprising the sequence of SEQ ID NO: 366, a HCDR2        comprising the sequence of SEQ ID NO: 367, a HCDR3 comprising        the sequence of SEQ ID NO: 368, a LCDR1 comprising the sequence        of SEQ ID NO: 369, a LCDR2 comprising the sequence of SEQ ID NO:        370, a LCDR3 comprising the sequence of SEQ ID NO: 371;    -   jj. HCDR1 comprising the sequence of SEQ ID NO: 376, a HCDR2        comprising the sequence of SEQ ID NO: 377, a HCDR3 comprising        the sequence of SEQ ID NO: 378, a LCDR1 comprising the sequence        of SEQ ID NO: 379, a LCDR2 comprising the sequence of SEQ ID NO:        380, a LCDR3 comprising the sequence of SEQ ID NO: 381;    -   kk. HCDR1 comprising the sequence of SEQ ID NO: 386, a HCDR2        comprising the sequence of SEQ ID NO: 387, a HCDR3 comprising        the sequence of SEQ ID NO: 388, a LCDR1 comprising the sequence        of SEQ ID NO: 389, a LCDR2 comprising the sequence of SEQ ID NO:        390, a LCDR3 comprising the sequence of SEQ ID NO: 391;    -   ll. HCDR1 comprising the sequence of SEQ ID NO: 396, a HCDR2        comprising the sequence of SEQ ID NO: 397, a HCDR3 comprising        the sequence of SEQ ID NO: 398, a LCDR1 comprising the sequence        of SEQ ID NO: 399, a LCDR2 comprising the sequence of SEQ ID NO:        400, a LCDR3 comprising the sequence of SEQ ID NO: 401;    -   mm. HCDR1 comprising the sequence of SEQ ID NO: 406, a HCDR2        comprising the sequence of SEQ ID NO: 407, a HCDR3 comprising        the sequence of SEQ ID NO: 408, a LCDR1 comprising the sequence        of SEQ ID NO: 409, a LCDR2 comprising the sequence of SEQ ID NO:        410, a LCDR3 comprising the sequence of SEQ ID NO: 411;    -   nn. HCDR1 comprising the sequence of SEQ ID NO: 416, a HCDR2        comprising the sequence of SEQ ID NO: 417, a HCDR3 comprising        the sequence of SEQ ID NO: 418, a LCDR1 comprising the sequence        of SEQ ID NO: 419, a LCDR2 comprising the sequence of SEQ ID NO:        420, a LCDR3 comprising the sequence of SEQ ID NO: 421;    -   oo. HCDR1 comprising the sequence of SEQ ID NO: 426, a HCDR2        comprising the sequence of SEQ ID NO: 427, a HCDR3 comprising        the sequence of SEQ ID NO: 428, a LCDR1 comprising the sequence        of SEQ ID NO: 429, a LCDR2 comprising the sequence of SEQ ID NO:        430, a LCDR3 comprising the sequence of SEQ ID NO: 431; or

a combination thereof.

In some embodiments, the modified antibody or an antigen-bindingfragment thereof disclosed herein, wherein the antigen-binding domaincan comprise:

a HCDR1 comprising the sequence of SEQ ID NO: 105, a HCDR2 comprisingthe sequence of SEQ ID NO: 106, a HCDR3 comprising the sequence of SEQID NO: 107, a LCDR1 comprising the sequence of SEQ ID NO: 108, a LCDR2comprising the sequence of SEQ ID NO: 109, and a LCDR3 comprising thesequence of SEQ ID NO: 110;

a HCDR1 comprising the sequence of SEQ ID NO: 136, a HCDR2 comprisingthe sequence of SEQ ID NO: 137, a HCDR3 comprising the sequence of SEQID NO: 138, a LCDR1 comprising the sequence of SEQ ID NO: 139, a LCDR2comprising the sequence of SEQ ID NO: 140, and a LCDR3 comprising thesequence of SEQ ID NO: 141;

or a combination thereof.

In some embodiments, the modified antibody can comprise a firstantigen-binding domain comprising a HCDR1 comprising the sequence of SEQID NO: 105, a HCDR2 comprising the sequence of SEQ ID NO: 106, a HCDR3comprising the sequence of SEQ ID NO: 107, a LCDR1 comprising thesequence of SEQ ID NO: 108, a LCDR2 comprising the sequence of SEQ IDNO: 109, and a LCDR3 comprising the sequence of SEQ ID NO: 110; and asecond antigen-binding domain comprising a HCDR1 comprising the sequenceof SEQ ID NO: 136, a HCDR2 comprising the sequence of SEQ ID NO: 137, aHCDR3 comprising the sequence of SEQ ID NO: 138, a LCDR1 comprising thesequence of SEQ ID NO: 139, a LCDR2 comprising the sequence of SEQ IDNO: 140, and a LCDR3 comprising the sequence of SEQ ID NO: 141; andwherein the antibody comprises the modified human IgG constant domaincomprises a substitution with tyrosine at amino acid residue 252, asubstitution with threonine at amino acid residue 254, and asubstitution with glutamic acid at amino acid residue 256, numberedaccording to the EU index as in Kabat.

In some embodiments, the modified antibody or an antigen-bindingfragment thereof disclosed herein, wherein the modified antibody or theantigen-binding fragment can have a half-life (T_(1/2)) in a range offrom 50 to 120 days in vivo, such as in a human subject. The modifiedantibody or the antigen-binding fragment can have a half-life (T_(1/2))in a range of from 50 to 120 days, 60 to 120 days, 70 to 120 days, 80 to120 days, 90 to 120 days, 100 to 120 day, or 110 to 120 days.

In some embodiments, the modified antibody or an antigen-bindingfragment thereof disclosed herein, wherein the modified antibody cancomprise at least one amino acid subsequent substitutions in theantigen-binding domain, the human IgG constant domain, a light chain ofthe modified antibody, a heavy chain of the modified antibody, or acombination thereof. In some cases, the subsequent substitution cancomprise substituting a cystine residue to a non-cystine residue. Insome cases, the cystine residue can be substituted with a serineresidue. In some embodiments, a modified antibody can comprise a C106Ssubstitution, wherein the cystine 106 is substituted with a serine, inthe heavy chain variable region HDR3, numbered according to theinternational ImMunoGeneTics system (IMGT) unique numbering.

In some embodiments, a modified antibody can comprise an antigen-bindingdomain having an antigen-binding affinity and a covalently linkedmodified human IgG constant domain, wherein the antigen-binding affinitycomprises at least one of the LCDRs and at least one of the HCDRs listedin Table 1, wherein the modified human IgG constant domain comprises asubstitution with tyrosine at amino acid residue 252, a substitutionwith threonine at amino acid residue 254, and a substitution withglutamic acid at amino acid residue 256, numbered according to the EUindex as in Kabat, and a C106S substitution, wherein the cystine 106 issubstituted with a serine, in the heavy chain variable region HDR3,numbered according to the international ImMunoGeneTics system (IMGT)unique numbering. In some embodiments, a modified antibody can comprisean antigen-binding domain having an antigen-binding affinity and acovalently linked modified human IgG constant domain, wherein theantigen-binding affinity comprises HCDR SEQ ID No.: 136, SEQ ID No.:137, SEQ ID No.: 138, LCDR SEQ ID No.: 139, SEQ ID. No.: 140 and SEQ ID.No.: 141 (P2B-1G5), wherein the modified human IgG constant domaincomprises a substitution with tyrosine at amino acid residue 252, asubstitution with threonine at amino acid residue 254, and asubstitution with glutamic acid at amino acid residue 256, numberedaccording to the EU index as in Kabat, and a C106S substitution, whereinthe cystine 106 is substituted with a serine, in the heavy chainvariable region, numbered according to the international ImMunoGeneTicssystem (IMGT) unique numbering.

In some embodiments, the modified antibody or an antigen-bindingfragment thereof disclosed herein can further comprise one or moresubsequent modified antibodies selected from a first subsequent modifiedantibody comprising two antigen-binding domains each having a same ordifferent affinity to the SARS-CoV-2, a second subsequent modifiedantibody comprising a first antigen-binding domain having a bindingaffinity to the SARS-CoV-2 and a second antigen-binding domain having abinding affinity to a second pathogen that is different from theSARS-CoV-2, a third subsequent modified antibody comprising twoantigen-binding domains each having a binding affinity to the secondpathogen, or a combination thereof. The term “different affinities tothe SARS-CoV-2” refers affinity that can bind to a different epitope orbinding site of the SARS-CoV-2, a different affinity level that can bindto the same epitope or binding site of the SARS-CoV-2, or a combinationthereof.

In some embodiments, the modified antibody or an antigen-bindingfragment thereof disclosed herein, wherein the binding affinity to thesecond pathogen can be selected from a binding affinity to SARS-CoV,MERS-CoV, one or more bacteria, one or more fungus, one or more viruses,one or more parasites, a part thereof, or a combination thereof.

In some embodiments, the modified antibody or an antigen-bindingfragment thereof disclosed herein, wherein the modified antibody or theantigen-binding fragment thereof can be a single chain antibody, adiabody, a Fab, a Fab′, a F(ab′)2, a Fd, an Fv fragment, a disulfidestabilized Fv fragment (dsFv), a (dsFv)2, a bispecific dsFv(dsFv-dsFv′), a disulfide stabilized diabody (ds diabody), asingle-chain antibody molecule (scFv), an scFv dimer (bivalent diabody),a bispecific scFv dimer, a multispecific antibody, a heavy chainantibody, a camelized single domain antibody, a nanobody, a domainantibody, or a bivalent domain antibody, as disclosed above andhereafter.

Competitive Binding, Crystal Structure and Epitope

In one aspect, the present disclosure provides an isolated orrecombinant antibody or an antigen-binding fragment thereof, whichcompetes for binding to RBD of spike protein of SARS-CoV-2 with theantibody or an antigen-binding fragment thereof described herein.

Antibodies or antigen binding fragments that competes with the antibodyor antigen-binding fragment provided herein for binding to RBD of spikeprotein of SARS-CoV-2 include, but are not limited to, antibodies,antibody fragments and other binding agents that bind to an epitope orbinding site bound by the antibody or antigen-binding fragment providedherein, or bind to a sufficiently proximal epitope or binding site.Preferably, competitive antibodies or antigen binding fragments of thedisclosure will, when present in excess, inhibit specific binding of theantibody or antigen-binding fragment provided herein to RBD of the spikeprotein of SARS-CoV-2 by at least 10%, preferably by at least 25%, morepreferably by at least 50%, and most preferably by at least 75%-90% oreven greater. The identification of one or more competitive antibodiesor antigen binding fragments that bind to about, substantially,essentially or at the same epitope as the antibodies or antigen bindingfragments of the present disclosure is a straightforward technicalmatter. As the identification of competitive binding molecules isdetermined in comparison to a reference binding molecule, for example,the antibodies or antigen binding fragments of the present disclosure,it will be understood that actually determining the epitope to which thereference binding molecule and the competitive binding molecule bind isnot in any way required in order to identify a competitive bindingmolecule that binds to the same or substantially the same epitope as thereference binding molecule.

In one aspect, the present disclosure provides a crystal of RBD of thespike protein of SARS-CoV-2 in complex with an antibody. In certainembodiments, the antibody complexed with the RBD in the crystal is anyantibody provided herein, or an antigen-binding fragment thereof (e.g.an Fab fragment).

In some embodiment, the crystal provided herein comprises Fab fragmentof antibody P2B-2F6 in complex with RBD of the spike protein ofSARS-CoV-2. In some embodiment, the crystal consists of a P2₁2₁2₁ spacegroup with unit cell dimensions of a=70.23 Å, b=90.15 Å, and c=112.35 Å.

In some embodiment, the crystal provided herein comprises Fab fragmentof antibody P2C-1F11 in complex with RBD of the spike protein ofSARS-CoV-2. In some embodiment, the crystal has or consists of a C121space group with unit cell dimensions of a=194.88 Å, b=85.39 Å, andc=58.51 Å.

In some embodiment, the crystal provided herein comprises Fab fragmentof antibody P22A-1D1 in complex with RBD of the spike protein ofSARS-CoV-2. In some embodiment, the crystal has or consists of a C2space group with unit cell dimensions of a=193.34 Å, b=86.60 Å, andc=57.16 Å.

In some embodiment, the crystal provided herein comprises Fab fragmentof antibody P5A-1D2 in complex with RBD of the spike protein ofSARS-CoV-2. In some embodiment, the crystal has or consists of a C2space group with unit cell dimensions of a=158.75 Å, b=67.51 Å, andc=154.37 Å.

In some embodiment, the crystal provided herein comprises Fab fragmentof antibody P5A-3C8 in complex with RBD of the spike protein ofSARS-CoV-2. In some embodiment, the crystal has or consists of a P2₁2₁2₁space group with unit cell dimensions of a=112.54 Å, b=171.57 Å, andc=54.87 Å.

X-ray crystallography analysis of the antibody bound to RBD of the spikeprotein of SARS-CoV-2 can be used to determine antibody epitopes.Epitopes may, in particular, be identified in this way by determiningresidues on RBD of the spike protein of SARS-CoV-2 within 4 Å of anantibody paratope residue. In another aspect, the present disclosureprovides an isolated or recombinant antibody or an antigen-bindingfragment thereof, which specifically binds to an epitope on RBD of spikeprotein of SARS-CoV-2, wherein the epitope comprises at least one (atleast two, three, four, five, six, seven, eight, nine, ten, eleven, ortwelve) residues selected from K444, G446, G447, N448, Y449, N450, L452,V483, E484, G485, F490 and S494, wherein the residue numbering isaccording to SEQ ID NO: 134. In certain embodiments, the epitopecomprises Y449, L452, and F490. In certain embodiments, the epitopecomprises Y449, and G446. In certain embodiments, the antibody or anantigen-binding fragment thereof provided herein has a binding affinity(K_(d)) to the RBD of spike protein of SARS-CoV-2 of no more than 50 nM(e.g. no more than 40 nM, no more than 30 nM, no more than 20 nM, nomore than 10 nM, or no more than 5 nM), as measured by Surface Plasmonresonance (SPR).

In another aspect, the present disclosure provides an isolated orrecombinant antibody or an antigen-binding fragment thereof, whichspecifically binds to an epitope on RBD of spike protein of SARS-CoV-2,wherein the epitope comprises at least one (at least two, three, four,five, six, seven, eight, nine, ten, eleven, or twelve) residues selectedfrom Y453, L455, F456, R457, K458, 5459, N460, Y473, A475, G476, 5477,F486, N487, Y489, Q493, G502, Y505, R403, T415, G416, K417, D420 andY421, wherein the residue numbering is according to SEQ ID NO: 134. Incertain embodiments, the epitope comprises at least one (at least two,three, four, five, six, seven, eight, nine, ten, eleven, or twelve)residues selected from Y453, L455, F456, R457, K458, S459, N460, Y473,A475, G476, S477, F486, N487, Y489, Q493, G502 and Y505, wherein theresidue numbering is according to SEQ ID NO: 134. In certainembodiments, the epitope comprises or further comprises at least one (atleast two, three, four, five, or six) residues selected from R403, T415,G416, K417, D420 and Y421, wherein the residue numbering is according toSEQ ID NO: 134. In certain embodiments, the epitope comprises at leastone (at least two, three, four, five, six, seven, eight, nine, ten,eleven, twelve) residues selected from T415, G416, K417, D420, Y421,L455, F456, R457, K458, N460, Y473, A475, G476, S477, F486, N487, Y489and Q493, wherein the residue numbering is according to SEQ ID NO: 134.In certain embodiments, the epitope comprises at least one (at leasttwo, three, four, five, six, seven, eight, nine, ten, eleven, or twelve)residues selected from T415, G416, K417, D420, Y421, Y453, L455, F456,R457, K458, N460, Y473, Q474, A475, G476, S477, N487, Y489, Q493 andY505, wherein the residue numbering is according to SEQ ID NO: 134. Incertain embodiments, the epitope comprises at least one (at least two,three, four, five, six, seven, eight, nine, ten, eleven, or twelve)residues selected from T415, G416, K417, D420, Y421, Y453, L455, F456,R457, K458, N460, Y473, A475, G476, S477, F486, N487, Y489 and Q493,wherein the residue numbering is according to SEQ ID NO: 134. In certainembodiments, the epitope comprises at least one (at least two, three,four, five, six, seven, eight, nine, ten, eleven, or twelve) residuesselected from T415, G416, K417, D420, Y421, L455, F456, R457, K458,N460, Y473, Q474, A475, G476, S477, F486, N487, Y489 and Q493, whereinthe residue numbering is according to SEQ ID NO: 134. In certainembodiments, the epitope comprises at least one (at least two, three,four, five, six or seven) residues selected from L455, K458, Y473, A475,G476, S477 and N487. In certain embodiments, the epitope comprises atleast one (at least two, three, four, five, six or seven) residuesselected from T415, G416, K417, D420, Y421, K458 and N460. In certainembodiments, the epitope comprises at least one or at least two Y449,and G446. In certain embodiments, the epitope comprises at least one (atleast two, three or four) residues selected from K417, Y421, L455 andF456. In certain embodiments, the epitope comprises at least one (atleast two, three, or four) residues selected from F456, N487, Y489 andQ493. In certain embodiments, the epitope comprises L455. In certainembodiments, the epitope comprises at least one or at least two residuesselected from Y421 and D420. In certain embodiments, the epitopecomprises Y421. In certain embodiments, the epitope comprises Y505. Incertain embodiments, the epitope comprises Y421A and F456A, wherein theresidue numbering is according to SEQ ID NO: 134. In certainembodiments, the epitope comprises T415A, Y473A, and N487A, wherein theresidue numbering is according to SEQ ID NO: 134. In certainembodiments, the epitope comprises K417A, D420A, L455A, R457A, N460A,and Y489A, wherein the residue numbering is according to SEQ ID NO: 134.In certain embodiments, the epitope comprises T415A, Y421A, L455A,F456A, R457A, Y473A, N487A, Y489A, and Y505A, wherein the residuenumbering is according to SEQ ID NO: 134. In certain embodiments, theantibody or an antigen-binding fragment thereof provided herein has abinding affinity (K_(d)) to the RBD of spike protein of SARS-CoV-2 of nomore than 50 nM (e.g. no more than 40 nM, no more than 30 nM, no morethan 20 nM, or no more than 10 nM, or no more than 5 nM), as measured bySurface Plasmon resonance (SPR).

In an aspect, the present disclosure provides a computer-implementedmethod for causing a display of a graphical three-dimensionalrepresentation of the structure of a portion of a crystal of RBD of thespike protein of SARS-CoV-2 in complex with an anti-SARS-CoV-2 antibodyor an antigen-binding fragment thereof provided herein, wherein themethod comprises: causing said display of said graphicalthree-dimensional representation by a computer system programmed withinstructions for transforming structure coordinates into said graphicalthree-dimensional representation of said structure and for displayingsaid graphical three-dimensional representation, wherein said graphicalthree-dimensional representation is generated by transforming saidstructure coordinates into said graphical three-dimensionalrepresentation of said structure, wherein said structure coordinatescomprise structure coordinates of the backbone atoms of the portion ofthe crystal, wherein the portion of the crystal comprises a RBD bindingsite, and wherein the crystal has the space group symmetry P2₁2₁2₁ orC121.

In another aspect, the present disclosure provides a machine-readabledata storage medium comprising a data storage material encoded withmachine-readable instructions for: (a) transforming data into agraphical three-dimensional representation for the structure of aportion of a crystal of RBD of the spike protein of SARS-CoV-2 incomplex with an anti-SARS-CoV-2 antibody or an antigen-binding fragmentthereof provided herein; and (b) causing the display of said graphicalthree-dimensional representation; wherein said data comprise structurecoordinates of the backbone atoms of the amino acids defining a RBDbinding site; and wherein the crystal or structural homolog has thespace group symmetry P2₁2₁2₁ or C121.

In another aspect, the present disclosure provides a computer system fordisplaying a three-dimensional graphical representation for thestructure of a portion of a crystal of RBD of the spike protein ofSARS-CoV-2 in complex with an anti-SARS-CoV-2 antibody or anantigen-binding fragment thereof as provided herein, comprising: (a) amachine-readable data storage medium comprising a data storage materialencoded with machine-readable data, wherein said data comprise structurecoordinates of the backbone atoms of the amino acids defining a RBDbinding site, wherein the crystal has the space group symmetry P2₁2₁2₁or C121; (b) a working memory; (c) a central processing unit coupled tosaid working memory and to said machine-readable data storage medium forprocessing said machine-readable data into sad three-dimensionalgraphical representation; and (d) a display coupled to said centralprocessing unit for displaying said three-dimensional graphicalrepresentation.

For the above listed aspects, in certain embodiments, the RBD comprisesan amino acid sequence as shown in SEQ ID NO: 124. In certainembodiments, the antibody comprises a pair of heavy chain variableregion and light chain variable region as listed in Table 2, or thehomologous sequence thereof (e.g. having at least 80% sequenceidentity). In certain embodiments, the antibody comprises: a) a heavychain variable region of SEQ ID NO: 47 and a light chain variable regionof SEQ ID NO: 48; orb) a heavy chain variable region of SEQ ID NO: 111and a light chain variable region of SEQ ID NO: 112; or c) a heavy chainvariable region of SEQ ID NO: 432 and a light chain variable region ofSEQ ID NO: 433; or d) a heavy chain variable region of SEQ ID NO: 242and a light chain variable region of SEQ ID NO: 243; or e) a heavy chainvariable region of SEQ ID NO: 232 and a light chain variable region ofSEQ ID NO: 233. In certain embodiments, the structure coordinatescomprise the structure coordinates of the backbone atoms of the aminoacid residues corresponding to K444, G446, G447, N448, Y449, N450, L452,V483, E484, G485, F490 and/or S494 of the RBD, wherein the residuenumbering is according to SEQ ID NO: 134. In certain embodiments, thestructure coordinates comprise the structure coordinates of the backboneatoms of the amino acid residues corresponding to Y453, L455, F456,R457, K458, S459, N460, Y473, A475, G476, S477, F486, N487, Y489, Q493,G502, Y505, R403, T415, G416, K417, D420 and/or Y421 of the RBD, whereinthe residue numbering is according to SEQ ID NO: 134. In certainembodiments, the structure coordinates comprise the structurecoordinates of the backbone atoms of the amino acid residuescorresponding to T415, G416, K417, D420, Y421, L455, F456, R457, K458,N460, Y473, A475, G476, S477, F486, N487, Y489 and/or Q493 of the RBD,wherein the residue numbering is according to SEQ ID NO: 134. In certainembodiments, the structure coordinates comprise the structurecoordinates of the backbone atoms of the amino acid residuescorresponding to T415, G416, K417, D420, Y421, Y453, L455, F456, R457,K458, N460, Y473, Q474, A475, G476, S477, N487, Y489, Q493 and/or Y505of the RBD, wherein the residue numbering is according to SEQ ID NO:134. In certain embodiments, the structure coordinates comprise thestructure coordinates of the backbone atoms of the amino acid residuescorresponding to T415, G416, K417, D420, Y421, Y453, L455, F456, R457,K458, N460, Y473, A475, G476, 5477, F486, N487, Y489 and/or Q493 of theRBD, wherein the residue numbering is according to SEQ ID NO: 134. Incertain embodiments, the structure coordinates comprise the structurecoordinates of the backbone atoms of the amino acid residuescorresponding to T415, G416, K417, D420, Y421, L455, F456, R457, K458,N460, Y473, Q474, A475, G476, S477, F486, N487, Y489 and/or Q493 of theRBD, wherein the residue numbering is according to SEQ ID NO: 134.

In another aspect, the present disclosure provides a method of screeningfor molecules that may be a binding molecule of RBD of the spike proteinof SARS-CoV-2, comprising: (a) computationally screening agents againsta three-dimensional model to identify potential binding molecules of theRBD; wherein the three-dimensional model comprises a three-dimensionalmodel of at least a portion of a crystal of RBD of the spike protein ofSARS-CoV-2 in complex with an anti-SARS-CoV-2 antibody or anantigen-binding fragment thereof; wherein the three dimensional model isgenerated from at least a portion of the structure coordinates of thecrystal by a computer algorithm for generating a three-dimensional modelof the crystal useful for identifying agents that are potential bindingmolecules of the RBD.

In certain embodiments, the crystal comprises a polypeptide comprisingan amino acid sequence SEQ ID NO: 124, or a homologous sequence thereof,for example derived from a mutant SARS-CoV-2. In certain embodiments,the crystal further comprises an antibody or antigen-binding fragmentthereof comprising a pair of heavy chain variable region and light chainvariable region as listed in Table 2, or the homologous sequence thereof(e.g. having at least 80% sequence identity). In certain embodiments,the crystal further comprises an antibody or antigen-binding fragmentthereof comprising: a) a heavy chain variable region of SEQ ID NO: 47and a light chain variable region of SEQ ID NO: 48, or b) a heavy chainvariable region of SEQ ID NO: 111 and a light chain variable region ofSEQ ID NO: 112, wherein the crystal diffracts x-rays for thedetermination of atomic coordinates to a resolution of 5 Å or better.

A method for obtaining structural information about a molecule ormolecular complex comprising applying at least a portion of thestructure coordinates of a RBD of the spike protein of SARS-CoV-2 incomplex with an anti-SARS-CoV-2 antibody or an antigen-binding fragmentthereof provided herein, to an X-ray diffraction pattern of the moleculeor molecular complex's crystal structure to cause the generation of athree-dimensional electron density map of at least a portion of themolecule or molecular complex. In certain embodiments, the crystalcomprises a polypeptide comprising an amino acid sequence SEQ ID NO:124, or a homologous sequence thereof, for example derived from a mutantSARS-CoV-2. In certain embodiments, the crystal further comprises anantibody or antigen-binding fragment thereof comprising a pair of heavychain variable region and light chain variable region as listed in Table2, or the homologous sequence thereof (e.g. having at least 80% sequenceidentity). In certain embodiments, the crystal further comprises anantibody or antigen-binding fragment thereof comprising: a) a heavychain variable region of SEQ ID NO: 47 and a light chain variable regionof SEQ ID NO: 48, orb) a heavy chain variable region of SEQ ID NO: 111and a light chain variable region of SEQ ID NO: 112, wherein the crystaldiffracts x-rays for the determination of atomic coordinates to aresolution of 5 Å or better.

Conjugates

In some embodiments, the anti-SARS-CoV-2 antibodies or antigen-bindingfragments thereof further comprise one or more conjugate moieties. Aconjugate moiety is a moiety that can be attached to the antibodies orantigen-binding fragments thereof either directly or via a linker orthrough another conjugate moiety. It is contemplated that a variety ofconjugate moieties may be linked to the antibodies or antigen-bindingfragments thereof provided herein (see, for example, “ConjugateVaccines”, Contributions to Microbiology and Immunology, J. M. Cruse andR. E. Lewis, Jr. (eds.), Carger Press, New York, (1989)). Theseconjugate moieties may be linked to the antibodies or antigen-bindingfragments thereof by covalent binding, affinity binding, intercalation,coordinate binding, complexation, association, blending, or addition,among other methods.

In certain embodiments, the antibodies or antigen-binding fragmentsthereof provided herein may be engineered to contain specific sitesoutside the epitope binding portion that may be utilized for binding toone or more conjugate moieties. For example, such a site may include oneor more reactive amino acid residues, such as for example cysteine orhistidine residues, to facilitate covalent linkage to a conjugatemoiety.

Examples of such conjugate moieties include but are not limited to,therapeutic agent, a radioactive isotope, a detectable label, apharmacokinetic modifying moiety, or a purifying moiety. In someembodiments, the conjugate moiety comprises a clearance-modifying agent(e.g. a polymer such as PEG which extends half-life), a chemotherapeuticagent, a toxin, a radioactive isotope, a lanthanide, a detectable label(e.g. a luminescent label, a fluorescent label, an enzyme-substratelabel), a DNA-alkylator, a topoisomerase inhibitor, a tubulin-binder, apurification moiety or other anticancer drugs.

Examples of detectable label may include a fluorescent labels (e.g.fluorescein, rhodamine, dansyl, phycoerythrin, or Texas Red),enzyme-substrate labels (e.g. horseradish peroxidase, alkalinephosphatase, luceriferases, glucoamylase, lysozyme, saccharide oxidasesor β-D-galactosidase), radioisotopes (e.g. ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ³⁵S,³H, ¹¹¹In, ¹¹²In, ¹⁴C, ⁶⁴Cu, ⁶⁷Cu, ⁸⁶Y, ⁸⁸Y, ⁹⁰Y, ¹⁷⁷Lu, ²¹¹At, ¹⁸⁶Re,¹⁸⁸Re, ¹⁵³Sm, ²¹²Bi, and ³²P, other lanthanides), luminescent labels,chromophoric moieties, digoxigenin, biotin/avidin, DNA molecules or goldfor detection.

In certain embodiments, the conjugate moiety can be aclearance-modifying agent which helps increase half-life of theantibody. Illustrative example include water-soluble polymers, such asPEG, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of ethylene glycol/propylene glycol, and thelike. The polymer may be of any molecular weight, and may be branched orunbranched. The number of polymers attached to the antibody may vary,and if more than one polymer are attached, they can be the same ordifferent molecules. In certain embodiments, the conjugate moiety can bea purification moiety such as a magnetic bead. In certain embodiments,the antibodies or antigen-binding fragments thereof provided herein isused as a base for a conjugate.

Polynucleotides and Recombinant Methods

The present disclosure provides isolated polynucleotides that encode theanti-SARS-CoV-2 antibodies or antigen-binding fragments thereof providedherein. DNA encoding the monoclonal antibody is readily isolated, e.g.,from B cells, and sequenced using conventional procedures (e.g. by usingoligonucleotide probes that are capable of binding specifically to genesencoding the heavy and light chains of the antibody). The encoding DNAmay also be obtained by synthetic methods.

The isolated polynucleotide that encodes the anti-SARS-CoV-2 antibodiesor antigen-binding fragments thereof can be inserted into a vector forfurther cloning (amplification of the DNA) or for expression (i.e.,expression vector), using recombinant techniques known in the art. Manyvectors are available. The vector components generally include, but arenot limited to, one or more of the following: a signal sequence, anorigin of replication, one or more marker genes, an enhancer element, apromoter (e.g. SV40, CMV, EF-1α), and a transcription terminationsequence.

The present disclosure provides vectors comprising the isolatedpolynucleotide provided herein. In certain embodiments, thepolynucleotide provided herein encodes the antibodies or antigen-bindingfragments thereof, at least one promoter (e.g. SV40, CMV, EF-1α)operably linked to the nucleic acid sequence, and at least one selectionmarker. Examples of vectors include, but are not limited to, retrovirus(including lentivirus), adenovirus, adeno-associated virus, herpesvirus(e.g. herpes simplex virus), poxvirus, baculovirus, papillomavirus,papovavirus (e.g. SV40), lambda phage, and M13 phage, plasmid pcDNA3.3,pMD18-T, pOptivec, pCMV, pEGFP, pIRES, pQD-Hyg-GSeu, pALTER, pBAD,pcDNA, pCal, pL, pET, pGEMEX, pGEX, pCI, pEGFT, pSV2, pFUSE, pVITRO,pVIVO, pMAL, pMONO, pSELECT, pUNO, pDUO, Psg5L, pBABE, pWPXL, pBI,p15TV-L, pPro18, pTD, pRS10, pLexA, pACT2.2, pCMV-SCRIPT®, pCDM8,pCDNA1.1/amp, pcDNA3.1, pRc/RSV, PCR 2.1, pEF-1, pFB, pSG5, pXT1,pCDEF3, pSVSPORT, pEF-Bos etc.

Vectors comprising the polynucleotide sequence encoding the antibody orantigen-binding fragment thereof can be introduced to a host cell forcloning or gene expression. Suitable host cells for cloning orexpressing the DNA in the vectors herein are the prokaryote, yeast, orhigher eukaryote cells described above. Suitable prokaryotes for thispurpose include eubacteria, such as Gram-negative or Gram-positiveorganisms, for example, Enterobacteriaceae such as Escherichia, e.g. E.coli, Enterobacter, Envinia, Klebsiella, Proteus, Salmonella, e.g.Salmonella typhimurium, Serratia, e.g. Serratia marcescans, andShigella, as well as Bacilli such as B. subtilis and B. licheniformis,Pseudomonas such as P. aeruginosa, and Streptomyces.

In addition to prokaryotes, eukaryotic microbes such as filamentousfungi or yeast are suitable cloning or expression hosts foranti-SARS-CoV-2 antibody-encoding vectors. Saccharomyces cerevisiae, orcommon baker's yeast, is the most commonly used among lower eukaryotichost microorganisms. However, a number of other genera, species, andstrains are commonly available and useful herein, such asSchizosaccharomyces pombe; Kluyveromyces hosts such as, e.g. K. lactis,K. fragilis (ATCC 12,424), K. bulgaricus (ATCC 16,045), K. wickeramii(ATCC 24,178), K. waltii (ATCC 56,500), K. drosophilarum (ATCC 36,906),K. thermotolerans, and K. marxianus; yarrowia (EP 402,226); Pichiapastoris (EP 183,070); Candida; Trichoderma reesia (EP 244,234);Neurospora crassa; Schwanniomyces such as Schwanniomyces occidentalis;and filamentous fungi such as, e.g. Neurospora, Penicillium,Tolypocladium, and Aspergillus hosts such as A. nidulans and A. niger.

Suitable host cells for the expression of glycosylated antibodies orantigen-fragment thereof provided herein are derived from multicellularorganisms. Examples of invertebrate cells include plant and insectcells. Numerous baculoviral strains and variants and correspondingpermissive insect host cells from hosts such as Spodoptera frugiperda(caterpillar), Aedes aegypti (mosquito), Aedes albopictus (mosquito),Drosophila melanogaster (fruiffly), and Bombyx mori have beenidentified. A variety of viral strains for transfection are publiclyavailable, e.g. the L-1 variant of Autographa californica NPV and theBm-5 strain of Bombyx mori NPV, and such viruses may be used as thevirus herein according to the present invention, particularly fortransfection of Spodoptera frupperda cells. Plant cell cultures ofcotton, corn, potato, soybean, petunia, tomato, and tobacco can also beutilized as hosts.

However, interest has been greatest in vertebrate cells, and propagationof vertebrate cells in culture (tissue culture) has become a routineprocedure. Examples of useful mammalian host cell lines are monkeykidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); humanembryonic kidney line (293 or 293 cells subcloned for growth insuspension culture, Graham et al., J. Gen Virol. 36:59 (1977)); babyhamster kidney cells (BHK, ATCC CCL 10); Chinese hamster ovarycells/-DHFR (CHO, Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216(1980)); mouse sertoli cells (TM4, Mather, Biol. Reprod. 23:243-251(1980)); monkey kidney cells (CV1 ATCC CCL 70); African green monkeykidney cells (VERO-76, ATCC CRL-1587); human cervical carcinoma cells(HELA, ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34); buffalo ratliver cells (BRL 3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL75); human liver cells (Hep G2, HB 8065); mouse mammary tumor (MMT060562, ATCC CCL51); TRI cells (Mather et al., Annals N.Y. Acad. Sci.383:44-68 (1982)); MRC 5 cells; FS4 cells; and a human hepatoma line(Hep G2). In some embodiments, the host cell is a mammalian culturedcell line, such as CHO, BHK, NS0, 293 and their derivatives.

Host cells are transformed with the above-described expression orcloning vectors for anti-SARS-CoV-2 antibody production and cultured inconventional nutrient media modified as appropriate for inducingpromoters, selecting transformants, or amplifying the genes encoding thedesired sequences. In another embodiment, the antibody may be producedby homologous recombination known in the art. In certain embodiments,the host cell is capable of producing the antibody or antigen-bindingfragment thereof provided herein.

The present disclosure also provides a method of expressing the antibodyor an antigen-binding fragment thereof provided herein, comprisingculturing the host cell provided herein under the condition at which thevector of the present disclosure is expressed. The host cells used toproduce the antibodies or antigen-binding fragments thereof providedherein may be cultured in a variety of media. Commercially availablemedia such as Ham's F10 (Sigma), Minimal Essential Medium (MEM),(Sigma), RPMI-1640 (Sigma), and Dulbecco's Modified Eagle's Medium(DMEM), Sigma) are suitable for culturing the host cells. In addition,any of the media described in Ham et al., Meth. Enz. 58:44 (1979),Barnes et al., Anal. Biochem. 102:255 (1980), U.S. Pat. Nos. 4,767,704;4,657,866; 4,927,762; 4,560,655; or 5,122,469; WO 90/03430; WO 87/00195;or U.S. Pat. Re. 30,985 may be used as culture media for the host cells.Any of these media may be supplemented as necessary with hormones and/orother growth factors (such as insulin, transferrin, or epidermal growthfactor), salts (such as sodium chloride, calcium, magnesium, andphosphate), buffers (such as HEPES), nucleotides (such as adenosine andthymidine), antibiotics (such as GENTAMYCIN™ drug), trace elements(defined as inorganic compounds usually present at final concentrationsin the micromolar range), and glucose or an equivalent energy source.Any other necessary supplements may also be included at appropriateconcentrations that would be known to a person skilled in the art. Theculture conditions, such as temperature, pH, and the like, are thosepreviously used with the host cell selected for expression, and will beapparent to a person skilled in the art.

When using recombinant techniques, the antibody can be producedintracellularly, in the periplasmic space, or directly secreted into themedium. If the antibody is produced intracellularly, as a first step,the particulate debris, either host cells or lysed fragments, isremoved, for example, by centrifugation or ultrafiltration. Carter etal., Bio/Technology 10:163-167 (1992) describe a procedure for isolatingantibodies which are secreted to the periplasmic space of E. coli.Briefly, cell paste is thawed in the presence of sodium acetate (pH3.5), EDTA, and phenylmethylsulfonylfluoride (PMSF) over about 30 min.Cell debris can be removed by centrifugation. Where the antibody issecreted into the medium, supernatants from such expression systems aregenerally first concentrated using a commercially available proteinconcentration filter, for example, an Amicon or Millipore Pelliconultrafiltration unit. A protease inhibitor such as PMSF may be includedin any of the foregoing steps to inhibit proteolysis and antibiotics maybe included to prevent the growth of adventitious contaminants.

The anti-SARS-CoV-2 antibodies or antigen-binding fragments thereofprepared from the cells can be purified using, for example,hydroxylapatite chromatography, gel electrophoresis, dialysis,DEAE-cellulose ion exchange chromatography, ammonium sulfateprecipitation, salting out, and affinity chromatography, with affinitychromatography being the preferred purification technique.

In certain embodiments, Protein A immobilized on a solid phase is usedfor immunoaffinity purification of the antibody and antigen-bindingfragment thereof. The suitability of protein A as an affinity liganddepends on the species and isotype of any immunoglobulin Fc domain thatis present in the antibody. Protein A can be used to purify antibodiesthat are based on human gammal, gamma2, or gamma4 heavy chains (Lindmarket al., J. Immunol. Meth. 62:1-13 (1983)). Protein G is recommended forall mouse isotypes and for human gamma3 (Guss et al., EMBO J. 5:15671575 (1986)). The matrix to which the affinity ligand is attached ismost often agarose, but other matrices are available. Mechanicallystable matrices such as controlled pore glass orpoly(styrenedivinyl)benzene allow for faster flow rates and shorterprocessing times than can be achieved with agarose. Where the antibodycomprises a CH3 domain, the Bakerbond ABX™ resin (J. T. Baker,Phillipsburg, N.J.) is useful for purification. Other techniques forprotein purification such as fractionation on an ion-exchange column,ethanol precipitation, Reverse Phase HPLC, chromatography on silica,chromatography on heparin crosslinked, beaded-form of agarose SEPHAROSE™(trademark of GE Healthcare) chromatography on an anion or cationexchange resin (such as a polyaspartic acid column), chromatofocusing,SDS-PAGE, and ammonium sulfate precipitation are also availabledepending on the antibody to be recovered.

Following any preliminary purification step(s), the mixture comprisingthe antibody of interest and contaminants may be subjected to low pHhydrophobic interaction chromatography using an elution buffer at a pHbetween about 2.5-4.5, preferably performed at low salt concentrations(e.g. from about 0-0.25M salt).

Pharmaceutical Composition

The present disclosure further provides pharmaceutical compositionscomprising the anti-SARS-CoV-2 antibodies or antigen-binding fragmentsthereof and one or more pharmaceutically acceptable carriers.

The present disclosure further provides a pharmaceutical compositioncomprising at least one or more of the modified antibody or anantigen-binding fragment thereof disclosed herein, at least one nucleicacid encoding the modified antibody or the antigen-binding fragmentthereof, or a combination thereof, and one or more pharmaceuticallyacceptable carriers.

In some embodiments, the pharmaceutical composition comprises acombination of two or more antibodies or the antigen binding fragmentsof the present disclosure. In some embodiments, the pharmaceuticalcomposition comprises a combination of two or more monoclonalantibodies, each of which comprises heavy chain CDR sequences and lightchain CDR sequences derived from an antibody selected from the groupconsisting of P2A-1A8, P2A-1A9, P2B-2G11, P2A-1A10, P2A-1B3, P2B-2F6,P2B-2G4, P2C-1A3, P2C-1C8, P2C- 1C10, P2C-1D5, P2C-1F11, P2B-1G5,P2B-1A1, P2C-1D7, P2B-1A10, P2B-1D9, P2B-1E4, P2B-1G1, P4A-2D9, P5A-2G7,P5A-3C8, P5A-1D2, P5A-2F11, P5A-2E1, P5A-1C8, P1A-1C10, P4A-1H6,P4B-1F4, P5A-1B6, P5A-1B8, P5A-1B9, P5A-1D1, P5A-1D10, P5A-2D11,P5A-2G9, P5A-2H3, P5A-3A1, P5A-3A6, P5A-3B4, P5A-3C12, and P22A-1D1. Insome embodiments, the pharmaceutical composition comprises a firstantibody comprising heavy chain CDR sequences and light chain CDRsequences derived from P2C-1F11, and a second antibody comprising heavychain CDR sequences and light chain CDR sequences derived from antibodyP2B-2F6.

In some embodiments, the two or more antibodies or the antigen bindingfragments thereof bind to different epitopes in RBD of spike protein ofSARS-CoV-2. In certain embodiments, the pharmaceutical compositioncomprises a first antibody which comprises P2C-1F11 or an antigenbinding fragment thereof, and a second antibody which is selected fromthe group consisting of P2C-1A3, P2C-1C10, P2B-2F6, P2B-1G5, andP2A-1B3, or an antigen binding fragment thereof. In certain embodiments,the pharmaceutical composition comprises a first antibody whichcomprises P2C-1A3 or an antigen binding fragment thereof, and a secondantibody which is selected from the group consisting of P5A-3C8,P5A-1D2, P22A-1D1, P2C-1F11, and P2A-1B3, or an antigen binding fragmentthereof In certain embodiments, the pharmaceutical composition comprisesa first antibody which comprises P2B-2F6 or an antigen binding fragmentthereof, and a second antibody selected from the group consisting ofP2C-1C10, P2C-1F11, P2B-1G5, and P2A-1B3, or an antigen binding fragmentthereof. In certain embodiments, the pharmaceutical compositioncomprises a first antibody which comprises P2A-1B3 or an antigen bindingfragment thereof, and a second antibody selected from the groupconsisting of P5A-3C8, P5A-1D2, P22A-1D1, P2C-1A3, P2C-1C10, P2C-1F11,P2B-2F6, and P2A-1A10, or an antigen binding fragment thereof. In someembodiments, the pharmaceutical composition comprises a first antibodywhich comprises P2C-1C10 or an antigen binding fragment thereof, and asecond antibody selected from the group consisting of P5A-3C8, P5A-1D2,P22A-1D1, P2C-1A3, P2C-1F11, and P2A-1B3, or an antigen binding fragmentthereof.

The present disclosure further provides pharmaceutical compositionscomprising the polynucleotides encoding the anti-SARS-CoV-2 antibodiesor the antigen-binding fragments thereof, and one or morepharmaceutically acceptable carriers. The present disclosure furtherprovides pharmaceutical compositions comprising the polynucleotidesencoding the combination of the two or more anti-SARS-CoV-2 antibodiesor the antigen-binding fragments thereof, and one or morepharmaceutically acceptable carriers.

The present disclosure further provides pharmaceutical compositionscomprising an expression vector comprising the polynucleotides encodingthe one or more of anti-SARS-CoV-2 antibodies or the antigen-bindingfragments thereof, and one or more pharmaceutically acceptable carriers.

In certain embodiments, the expression vector comprises a viral vectoror a non-viral vector. Examples of viral vectors include, withoutlimitation, adeno-associated virus (AAV) vector, lentivirus vector,retrovirus vector, and adenovirus vector. Examples of non-viral vectorsinclude, without limitation, naked DNA, plasmid, exosome, mRNA, and soon. In certain embodiments, the expression vector is suitable for genetherapy in human. Suitable vectors for gene therapy include, forexample, adeno-associated virus (AAV), or adenovirus vector. In certainembodiments, the expression vector comprises a DNA vector or a RNAvector. In certain embodiments, the pharmaceutically acceptable carriersare polymeric excipients, such as without limitation, microspheres,microcapsules, polymeric micelles and dendrimers. The polynucleotides,or polynucleotide vectors of the present disclosure may be encapsulated,adhered to, or coated on the polymer-based components by methods knownin the art (see for example, W. Heiser, Nonviral gene transfertechniques, published by Humana Press, 2004; U.S. Pat. No. 6,025,337;Advanced Drug Delivery Reviews, 57(15): 2177-2202 (2005)).

In some embodiments, the pharmaceutical composition further comprises asecond bioactive agent, such as a second therapeutic agent or a secondprophylactic agent.

Pharmaceutical acceptable carriers for use in the pharmaceuticalcompositions disclosed herein may include, for example, pharmaceuticallyacceptable liquid, gel, or solid carriers, aqueous vehicles, nonaqueousvehicles, antimicrobial agents, isotonic agents, buffers, antioxidants,anesthetics, suspending/dispending agents, sequestering or chelatingagents, diluents, adjuvants, excipients, or non-toxic auxiliarysubstances, other components known in the art, or various combinationsthereof.

Suitable components may include, for example, antioxidants, fillers,binders, disintegrants, buffers, preservatives, lubricants, flavorings,thickeners, coloring agents, emulsifiers or stabilizers such as sugarsand cyclodextrins. Suitable antioxidants may include, for example,methionine, ascorbic acid, EDTA, sodium thiosulfate, platinum, catalase,citric acid, cysteine, thioglycerol, thioglycolic acid, thiosorbitol,butylated hydroxanisol, butylated hydroxytoluene, and/or propyl gallate.As disclosed herein, inclusion of one or more antioxidants such asmethionine in a composition comprising an antibody or antigen-bindingfragment thereof and conjugates provided herein decreases oxidation ofthe antibody or antigen-binding fragment thereof. This reduction inoxidation prevents or reduces loss of binding affinity, therebyimproving antibody stability and maximizing shelf-life. Therefore, incertain embodiments, pharmaceutical compositions are provided thatcomprise one or more antibodies or antigen-binding fragments thereof asdisclosed herein and one or more antioxidants such as methionine.Further provided are methods for preventing oxidation of, extending theshelf-life of, and/or improving the efficacy of an antibody orantigen-binding fragment provided herein by mixing the antibody orantigen-binding fragment with one or more antioxidants such asmethionine.

To further illustrate, pharmaceutical acceptable carriers may include,for example, aqueous vehicles such as sodium chloride injection,Ringer's injection, isotonic dextrose injection, sterile waterinjection, or dextrose and lactated Ringer's injection, nonaqueousvehicles such as fixed oils of vegetable origin, cottonseed oil, cornoil, sesame oil, or peanut oil, antimicrobial agents at bacteriostaticor fungistatic concentrations, isotonic agents such as sodium chlorideor dextrose, buffers such as phosphate or citrate buffers, antioxidantssuch as sodium bisulfate, local anesthetics such as procainehydrochloride, suspending and dispersing agents such as sodiumcarboxymethylcelluose, hydroxypropyl methylcellulose, orpolyvinylpyrrolidone, emulsifying agents such as nonionic surfactantPolysorbate 80 (TWEEN®-80, TWEEN is a registered trademark of CRODAAMERICAS LLC), sequestering or chelating agents such as EDTA(ethylenediaminetetraacetic acid) or EGTA (ethylene glycol tetraaceticacid), ethyl alcohol, polyethylene glycol, propylene glycol, sodiumhydroxide, hydrochloric acid, citric acid, or lactic acid. Antimicrobialagents utilized as carriers may be added to pharmaceutical compositionsin multiple-dose containers that include phenols or cresols, mercurials,benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acidesters, thimerosal, benzalkonium chloride and benzethonium chloride.Suitable excipients may include, for example, water, saline, dextrose,glycerol, or ethanol. Suitable non-toxic auxiliary substances mayinclude, for example, wetting or emulsifying agents, pH bufferingagents, stabilizers, solubility enhancers, or agents such as sodiumacetate, sorbitan monolaurate, triethanolamine oleate, or cyclodextrin.

The pharmaceutical compositions can be a liquid solution, suspension,emulsion, pill, capsule, tablet, sustained release formulation, orpowder. Oral formulations can include standard carriers such aspharmaceutical grades of mannitol, lactose, starch, magnesium stearate,polyvinyl pyrollidone, sodium saccharine, cellulose, magnesiumcarbonate, etc.

The form of pharmaceutical compositions depends on a number of criteria,including, but not limited to, route of administration, extent ofdisease, or dose to be administered. The pharmaceutical compositions canbe formulated for intravenous, oral, nasal, rectal, percutaneous, orintramuscular administration. For example, dosage forms for intravenousadministration, may be formulated as lyophilized powder or fluidformulation; dosage forms for nasal administration may conveniently beformulated as aerosols, solutions, drops, gels or dry powders. Inaccordance to the desired route of administration, the pharmaceuticalcompositions can be formulated in the form of tablets, capsule, pill,dragee, powder, granule, sachets, cachets, lozenges, suspensions,emulsions, solutions, syrups, aerosols (as a solid or in a liquidmedium), spray, inhalant, or suppository.

In certain embodiments, the pharmaceutical compositions are formulatedinto an injectable composition. The injectable pharmaceuticalcompositions may be prepared in any conventional form, such as forexample liquid solution, suspension, emulsion, or solid forms suitablefor generating liquid solution, suspension, or emulsion. Preparationsfor injection may include sterile and/or non-pyretic solutions ready forinjection, sterile dry soluble products, such as lyophilized powders,ready to be combined with a solvent just prior to use, includinghypodermic tablets, sterile suspensions ready for injection, sterile dryinsoluble products ready to be combined with a vehicle just prior touse, and sterile and/or non-pyretic emulsions. The solutions may beeither aqueous or nonaqueous.

In certain embodiments, unit-dose parenteral preparations are packagedin an ampoule, a vial or a syringe with a needle. All preparations forparenteral administration should be sterile and not pyretic, as is knownand practiced in the art.

In certain embodiments, a sterile, lyophilized powder is prepared bydissolving an antibody or antigen-binding fragment as disclosed hereinin a suitable solvent. The solvent may contain an excipient whichimproves the stability or other pharmacological components of the powderor reconstituted solution, prepared from the powder. Excipients that maybe used include, but are not limited to, water, dextrose, sorbital,fructose, corn syrup, xylitol, glycerin, glucose, sucrose or othersuitable agent. The solvent may contain a buffer, such as citrate,sodium or potassium phosphate or other such buffer known to a personskilled in the art at, in one embodiment, about neutral pH. Subsequentsterile filtration of the solution followed by lyophilization understandard conditions known to a person skilled in the art provides adesirable formulation. In one embodiment, the resulting solution will beapportioned into vials for lyophilization. Each vial can contain asingle dosage or multiple dosages of the anti-SARS-CoV-2 antibody orantigen-binding fragment thereof or composition thereof. Overfillingvials with a small amount above that needed for a dose or set of doses(e.g. about 10%) is acceptable so as to facilitate accurate samplewithdrawal and accurate dosing. The lyophilized powder can be storedunder appropriate conditions, such as at about 4° C. to roomtemperature.

Reconstitution of a lyophilized powder with water for injection providesa formulation for use in parenteral administration. In one embodiment,for reconstitution the sterile and/or non-pyretic water or other liquidsuitable carrier is added to lyophilized powder. The precise amountdepends upon the selected therapy being given, and can be empiricallydetermined.

The pharmaceutical composition disclosed herein can comprise themodified antibody or an antigen-binding fragment thereof at aconcentration in a range of from a concentration in a range of from 10mg/mL to 150 mg/mL. The concentration of the modified antibody or anantigen-binding fragment thereof can be determined based on totalprotein concentration, antibody specific protein concentration, or acombination thereof. Typical measurement method for measuring proteinconcentrations known to those skilled in the art can be suitable.

In some embodiments, the pharmaceutical composition can be configured tobe administered to a subject via intravenous injection (IV),intramuscular injection (IM), subcutaneous (SC) injection, or acombination thereof.

In some embodiments, the pharmaceutical composition can be configuredfor preventing a disease in a person having no symptoms or free fromknown infections of the SARS-CoV-2, or treatment of a patient being asymptomatic non-hospitalized person of any age or an adult with COVID-19caused by SARS-CoV-2 infection, aged 60 years and older, any age havingat least one of the following conditions selected from smoking,exogenous or endogenous immunosuppression having HIV infection with CD4count <200 cells/mm³, receiving corticosteroids equivalent to prednisone≥20 mg daily for at least 14 consecutive days within 30 days prior to beadministered with the pharmaceutical composition, receiving one or morebiologics therapeutical agents, one or more immunomodulators, cancerchemotherapy within 90 days prior to be administered with thepharmaceutical composition; having chronic lung disease, chronic asthma;obesity with body mass index [BMI]>35, having symptoms of COVID-19selected from fever, cough, sore throat, malaise, headache, muscle pain,nausea, vomiting, diarrhea, loss of taste and smell, or a combinationthereof, having shortness of breath, dyspnea, or abnormal chest imaging,having evidence of lower respiratory disease during clinical assessmentor imaging, having saturation of oxygen (SpO2) ≥94% on room air at sealevel, having severe symptoms of the infection of the SARS-CoV-2, havingSpO2 <94% on room air at sea level, having a ratio of arterial partialpressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mmHg,respiratory frequency>30 breaths per minute, lung infiltrates >50%,having active symptoms of antibody-dependent enhancement (ADE), having ahistory of antibody-dependent enhancement (ADE), being allergic to anantibody treatment, being a hospital inpatient requiring supportivemanagement of complications of severe infection of the SARS-CoV-2selected from pneumonia, hypoxemic respiratory failure/ARDS, sepsis andseptic shock, cardiomyopathy and arrhythmia, acute kidney injury, andcomplications from prolonged hospitalization including secondarybacterial and fungal infections, thromboembolism, gastrointestinalbleeding, critical illness polyneuropathy/myopathy, or a combinationthereof.

In some embodiments, the pharmaceutical composition can further compriseone or more bioactive agent that can comprise a therapeutic agent or aprophylactic agent selected from an anti-viral agent, an antiviralpeptide, an anti-viral antibody, an anti-viral compound, an anti-viralcytokine, an anti-viral oligonucleotide, an RNA dependent RNA polymeraseinhibitor, a non-nucleoside reverse transcriptase inhibitor (NNRTI),nucleoside reverse transcriptase inhibitor (NRTI), purine nucleoside,antiviral interferon, adamantine antiviral compound, remdesivir,chloroquine, hydroxychloroquine, lopinavir, ritonavir, APN01, favilavir,mesalazine, toremifene, eplerenone, paroxetine, sirolimus, dactinomycin,irbesartan, emodin, mercaptopurine, melatonin, quinacrine, carvedilol,colchicine, camphor, equilin, oxymetholone, nafamosta, camostat,baricitinib, darunavir, ribavirin, galidesivir, BCX-4430, Arbidol,nitazoxanide, one or more derivatives thereof, or any combinationthereof. In some cases, the pharmaceutical composition can furthercomprise infliximab, abalizumab, ustekinumab, immunomodulators such asmethotrexate, 6MP, azathioprine, or a combination thereof. chronic

Methods of Treatment or Prevention

The present disclosure also provides methods of treating SARs-CoV-2infection or a disease, disorder or condition associated with SARs-CoV-2infection in a subject, comprising administering to the subject atherapeutically effective amount of one or more of the antibody orantigen-binding fragment thereof provided herein, or one or morepolynucleotides encoding one or more of the antibody or antigen-bindingfragment thereof provided herein, or the pharmaceutical compositionprovided herein.

In certain embodiments, the therapeutically effective amount can be anamount effective to decrease SARs-COV-2 titers, or to alleviate one ormore disease symptoms, viremia, or any other measurable manifestation ofSARS-CoV-2 infection in the treated subject or population, whether byinducing the regression of or inhibiting the progression of symptom(s)associated with SARs-COV-2 infection by any clinically measurabledegree. Decrease in SARs-COV-2 titers can be measured in the lung, forexample, by the concentration of SARs-COV-2 in sputum samples or alavage from the lungs from a mammal. Alleviation of a disease symptomcan be assessed by any clinical measurement typically used by physiciansor other skilled healthcare providers to assess the severity orprogression status of that symptom. Exemplary symptoms associated withSARs-COV-2 infection include, without limitation, fever, dry cough,shortness in breath, pain or pressure in the chest, new confusion orinability to arouse, bluish lips or face, loss of sense of smell and/orloss of sense of taste.

A subject in need of treatment include, for example, those alreadyinfected with SARS-CoV-2 (symptomatic or asymptomatic) or inflicted witha condition resulting from infection of SARS-CoV-2. Subjects partiallyor totally recovered from infection of SARS-CoV-2 might also be in needof treatment. In certain embodiments, the subject is human.

The present disclosure also provides methods of preventing SARs-CoV-2infection, or a disease, disorder or condition associated withSARs-COV-2 infection in a subject, comprising administering to thesubject a prophylactically effective amount of one or more of theantibody or antigen-binding fragment thereof provided herein, or one ormore polynucleotides encoding one or more of the antibody orantigen-binding fragment thereof provided herein, or the pharmaceuticalcomposition provided herein. Prevention encompasses inhibiting orreducing the spread of SARS-CoV-2 or inhibiting or reducing the onset,development or progression of one or more of the symptoms associatedwith infection with SARS-CoV-2.

In certain embodiments, the prophylactically effective amount can be anamount effective to neutralize SARs-COV-2 in the respiratory tract,lungs and/or other affected areas such as eyes, noses and mouth, inorder block infection, or effective to ameliorate at least one symptomassociated with SARs-COV-2 infection. Whether a symptom has beenameliorated can be assessed by any clinical measurement typically usedby physicians or other skilled healthcare providers to assess theseverity or progression status of that symptom or in certain instanceswill ameliorate the need for hospitalization.

A subject in need of prevention include, for example, those in whichinfection with SARS-CoV-2 is to be prevented, or those who are at riskfor SARS-CoV-2 infection. In certain embodiments, the subject is human.

The term “disease, disorder or condition associated with SARS-COV-2infection” as used herein include those that are caused by or related toSARs-COV-2 infection, such as, upper or lower respiratory tractinfections, pharyngitis, pneumonia, tracheobronchitis, bronchiolitis,bronchitis, acute respiratory distress syndrome, diarrhea, and anyrelated infections or inflammatory disorders.

The methods of treatment or prevention provided herein are also suitablefor gene therapy by transfer of polynucleotide sequences encoding theantibody product or fragment thereof in a subject, such that thepolynucleotide can be expressed in the subject to produce the antibodyin vivo. The polynucleotide provided herein can be administered to asubject by, for example, transfection techniques such as electroporationand hydrodynamic injection, which are suitable for administration ofnaked polynucleotides. For polynucleotides in the form of viral vectorssuch as AAV, it can be administered via local injection (e.g.intramuscular, intranasal, intradermal, subcutaneous, etc.) orsystematic administration (e.g. intravenous administration).

In certain embodiments, the methods can comprise administering to thesubject a therapeutically effective amount or a prophylacticallyeffective amount of a combination of two or more of the antibodies (orthe antigen-binding fragment thereof) provided herein. In certainembodiments, the two or more antibodies comprises a first antibodycomprising heavy chain CDR sequences and light chain CDR sequencesderived from P2C-1F11, and a second antibody comprising heavy chain CDRsequences and light chain CDR sequences derived from antibody P2B-2F6.In certain embodiments, the two or more antibodies or the antigenbinding fragments thereof bind to different epitopes in RBD of spikeprotein of SARS-CoV-2. In certain embodiments, the two or moreantibodies comprise a first antibody comprising P2C-1F11, and a secondantibody which is selected from the group consisting of P2C-1A3,P2C-1C10, P2B-2F6, P2B-1G5, and P2A-1B3. In certain embodiments, the twoor more antibodies comprise a first antibody comprising P2C-1A3 and asecond antibody which is selected from the group consisting of P5A-3C8,P5A-1D2, P22A-1D1, P2C-1F11, and P2A-1B3, or an antigen binding fragmentthereof. In certain embodiments, the two or more antibodies comprise afirst antibody comprising P2B-2F6 and a second antibody which isselected from the group consisting of P2C-1C10, P2C-1F11, P2B-1G5, andP2A-1B3, or an antigen binding fragment thereof. In certain embodiments,the two or more antibodies comprises a first antibody comprising P2A-1B3and a second antibody which selected from the group consisting ofP5A-3C8, P5A-1D2, P22A-1D1, P2C-1A3, P2C-1C10, P2C-1F11, P2B-2F6, andP2A-1A10, or an antigen binding fragment thereof. In some embodiments,the two or more antibodies comprise a first antibody which comprisesP2C-1C10 or an antigen binding fragment thereof, and a second antibodyselected from the group consisting of P5A-3C8, P5A-1D2, P22A-1D1,P2C-1A3, P2C-1F11, and P2A-1B3, or an antigen binding fragment thereof.

The antibodies or antigen-binding fragments thereof provided herein maybe administered by any route known in the art, such as for exampleparenteral (e.g. subcutaneous, intraperitoneal, intravenous, includingintravenous infusion, intramuscular, or intradermal injection) ornon-parenteral (e.g. oral, intranasal, intraocular, sublingual, rectal,or topical) routes.

In some embodiments, this disclosure is directed to a method fortreating or preventing a disease in a subject in need thereof, themethod can comprise administering an effective dosage of any one of thepharmaceutical compositions disclosed herein to the subject;

wherein the pharmaceutical composition can be configured to beadministered to the subject to maintain a plasma concentration of themodified antibody or an antigen-binding fragment thereof in atherapeutic effective range of from 10 μg/mL to 3500 μg/mL for a timeperiod in a range of from 1 day to 12 months after administering thepharmaceutical composition; and

wherein the subject can be infected with, exhibiting one or moresymptoms of being infected with, or at risk of being infected with theSARS-CoV-2.

The method disclosed herein can be used for preventing infection of theSARS-CoV-2 in a subject who is at risk of being infected, such as ahealthy person who may get in contact with another person who has or hadthe SARS-CoV-2 infection with or without symptoms, a person who providescase to or handles materials related from another person who has or hadthe SARS-CoV-2 infection with or without symptoms, such as a healthcarepersonnel, an emergency responder, a medical diagnosis servicepersonnel, a senior home service provider, or a combination thereof.

In some embodiments, the pharmaceutical composition can be administeredto the subject having no symptoms or free from known infections of theSARS-CoV-2, prior to the subject being infected with the SARS-CoV-2,prior to the subject exhibiting any symptoms of the infection of theSARS-CoV-2, or a combination thereof.

In some embodiments, the pharmaceutical composition can be configured tobe administered to the subject to maintain the plasma concentration ofthe modified antibody or an antigen-binding fragment thereof in atherapeutic effective range of from 10 μg/mL to 1500 μg/mL for a timeperiod ranging from 3 to 12 months after the administration and whereinthe administration is a single administration. In some embodiments, thepharmaceutical composition can be configured to be administered to thesubject to maintain the plasma concentration of the modified antibody oran antigen-binding fragment thereof in a therapeutic effective range offrom 10 μg/mL to 1500 μg/mL, 20 μg/mL to 1500 μg/mL, 30 μg/mL to 1500μg/mL, 40 μg/mL to 1500 μg/mL, 50 μg/mL to 1500 μg/mL, 60 μg/mL to 1500μg/mL, 70 μg/mL to 1500 μg/mL, 80 μg/mL to 1500 μg/mL, 90 μg/mL to 1500μg/mL, 100 μg/mL to 1500 μg/mL, 150 μg/mL to 1500 μg/mL, 200 μg/mL to1500 μg/mL, 300 μg/mL to 1500 μg/mL, 400 μg/mL to 1500 μg/mL, 500 μg/mLto 1500 μg/mL, 600 μg/mL to 1500 μg/mL, 700 μg/mL to 1500 μg/mL, 800μg/mL to 1500 μg/mL, 900 μg/mL to 1500 μg/mL, 1000 μg/mL to 1500 μg/mL,1100 μg/mL to 1500 μg/mL, 1200 μg/mL to 1500 μg/mL, 1300 μg/mL to 1500μg/mL or 1400 μg/mL to 1500 μg/mL, wherein the disclosure of theseranges is intended as a continuous range including every value betweenthe minimum and maximum values. In some embodiments, the time period canrange from 3 to 12 months, 4 to 12 months, 5 to 12 months, 6 to 12months, 7 to 12 months, 8 to 12 months, 9 to 12 months, 10 to 12 monthsor 11 to 12 months, after administration of the pharmaceuticalcomposition and wherein the administration can be a singleadministration. The plasma concentration of the modified antibody or anantigen-binding fragment thereof to reach the above mentioned rangewithin a day and can maintain within the above mentioned range for theindicated time periods disclosed above.

In some embodiments, the subject can be a person having no symptoms orfree from known infections of the SARS-CoV-2, or treatment of a patientbeing a symptomatic non-hospitalized adult with COVID-19 caused bySARS-CoV-2 infection, aged 60 years and older, any age having at leastone of the following conditions selected from smoking, exogenous orendogenous immunosuppression having HIV infection with CD4 count <200cells/mm3, receiving corticosteroids equivalent to prednisone ≥20 mgdaily for at least 14 consecutive days within 30 days prior to beadministered with the pharmaceutical composition, receiving one or morebiologics therapeutical agents, one or more immunomodulators, cancerchemotherapy within 90 days prior to be administered with thepharmaceutical composition; having chronic lung disease, chronic asthma;obesity with body mass index [BMI]>35, having symptoms of COVID-19selected from fever, cough, sore throat, malaise, headache, muscle pain,nausea, vomiting, diarrhea, loss of taste and smell, or a combinationthereof, having shortness of breath, dyspnea, or abnormal chest imaging,having evidence of lower respiratory disease during clinical assessmentor imaging, having saturation of oxygen (SpO2) ≥94% on room air at sealevel, having severe symptoms of the infection of the SARS-CoV-2, havingSpO2 <94% on room air at sea level, having a ratio of arterial partialpressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mmHg,respiratory frequency>30 breaths per minute, lung infiltrates >50%,having active symptoms of antibody-dependent enhancement (ADE), having ahistory of antibody-dependent enhancement (ADE), being allergic to anantibody treatment, being a hospital inpatient requiring supportivemanagement of complications of severe infection of the SARS-CoV-2selected from pneumonia, hypoxemic respiratory failure/ARDS, sepsis andseptic shock, cardiomyopathy and arrhythmia, acute kidney injury, andcomplications from prolonged hospitalization including secondarybacterial and fungal infections, thromboembolism, gastrointestinalbleeding, critical illness polyneuropathy/myopathy, or a combinationthereof.

In some embodiments, the subject can be a person 60 years and older, 65years and older, 70 years and older, 75 years and older, 80 years andolder, 85 years and older or 90 years and older.

In some embodiments of the method disclosed herein, the pharmaceuticalcomposition can be configured to be administered to the subject tomaintain the plasma concentration of the modified antibody or anantigen-binding fragment thereof in a therapeutic effective range offrom 30 μg/mL to 3500 μg/mL for a time period ranging from 1 to 4 weeksafter the administration and wherein the administration is a singleadministration. In some embodiments, the pharmaceutical composition canbe configured to be administered to the subject to maintain the plasmaconcentration of the modified antibody or an antigen-binding fragmentthereof in a therapeutic effective range of from 10 μg/mL to 3500 μg/mL,20 μg/mL to 3500 μg/mL, 30 μg/mL to 3500 μg/mL, 40 μg/mL to 3500 μg/mL,50 μg/mL to 3500 μg/mL, 60 μg/mL to 3500 μg/mL, 70 μg/mL to 3500 μg/mL,80 μg/mL to 3500 μg/mL, 90 μg/mL to 3500 μg/mL, 100 μg/mL to 3500 μg/mL,150 μg/mL to 3500 μg/mL, 200 μg/mL to 3500 μg/mL, 300 μg/mL to 3500μg/mL, 400 μg/mL to 3500 μg/mL, 500 μg/mL to 3500 μg/mL, 600 μg/mL to3500 μg/mL, 700 μg/mL to 3500 μg/mL, 800 μg/mL to 3500 μg/mL, 900 μg/mLto 3500 μg/mL, 1000 μg/mL to 3500 μg/mL, 1100 μg/mL to 3500 μg/mL, 1200μg/mL to 3500 μg/mL, 1300 μg/mL to 3500 μg/mL, 1400 μg/mL to 3500 μg/mL,1500 μg/mL to 3500 μg/mL, 1600 μg/mL to 3500 μg/mL, 1700 μg/mL to 3500μg/mL, 1800 μg/mL to 3500 μg/mL, 1900 μg/mL to 3500 μg/mL, 2000 μg/mL to3500 μg/mL, 2100 μg/mL to 3500 μg/mL, 2200 μg/mL to 3500 μg/mL, 2300μg/mL to 3500 μg/mL, 2400 μg/mL to 3500 μg/mL, 2500 μg/mL to 3500 μg/mL,2600 μg/mL to 3500 μg/mL, 2700 μg/mL to 3500 μg/mL, 2800 μg/mL to 3500μg/mL, 2900 μg/mL to 3500 μg/mL, 3000 μg/mL to 3500 μg/mL, 3100 μg/mL to3500 μg/mL, 3200 μg/mL to 3500 μg/mL, 3300 μg/mL to 3500 μg/mL or 3400μg/mL to 3500 μg/mL, wherein the disclosure of these ranges is intendedas a continuous range including every value between the minimum andmaximum values. In some embodiments, the time period can range from 1 to4 weeks, 2 to 4 weeks or 3 to 4 weeks after administration of thepharmaceutical composition and wherein the administration can be asingle administration. The plasma concentration of the modified antibodyor an antigen-binding fragment thereof to reach the above mentionedrange within a day and can maintain within the above mentioned range forthe indicated time periods disclosed above.

In some embodiments, the pharmaceutical composition can be administeredto maintain a high plasma concentration, such as 30 μg/mL to 3500 μg/mL,of the modified antibody or an antigen-binding fragment thereofimmediately after administration, such as 1 day to a few days or 1 to 4weeks, for treating a patient with the disease or symptoms of theinfection of the SARS-CoV-2. In some embodiments, the pharmaceuticalcomposition can be administered to maintain a desired plasmaconcentration, such as 10 μg/mL to 1500 μg/mL, of the modified antibodyor an antigen-binding fragment thereof and maintain within the desiredrange for 3 to 12 months, for preventing a person from being infectedwith the SARS-CoV-2. As used herein the “plasma concentration” or “serumconcentration” may be used interchangeably for the concentration of themodified antibody or an antigen-binding fragment thereof in the blood ofa patient.

In some embodiments, plasma concentration of the modified antibody or anantigen-binding fragment thereof can be at about 100-300 times of invitro IC₉₀ for at least 3 to 6 weeks for treating a patient with theSARS-CoV-2 infection or symptoms of the SARS-CoV-2 infection. In someembodiments, plasma concentration of the modified antibody or anantigen-binding fragment thereof can be at about 10-50 times of in vitroIC₉₀ for at least 6-month for preventing the SARS-CoV-2 infection orsymptoms of the SARS-CoV-2 infection.

In some embodiments of the method disclosed herein, the modifiedantibody or the antigen-binding fragment thereof can be configured tohave a half-life (T_(1/2)) in a range of from 50 to 120 days in thesubject. In some embodiments, the half-life (T_(1/2)) can be in a rangeof from 50 to 120 days, 60 to 120 days, 70 to 120 days, 80 to 120 days,90 to 120 days, 100 to 120 days or 110 to 120 days, in the subject.

In some embodiments of the method disclosed herein, the pharmaceuticalcomposition can be configured to be administered to the subject in arange of from 150 mg/m² to 5000 mg/m². In some cases, the pharmaceuticalcomposition can be administered to the subject in a dosage range of from150 to 5000 mg/m², 200 to 5000 mg/m², 300 to 5000 mg/m², 400 to 5000mg/m², 500 to 5000 mg/m², 600 to 5000 mg/m², 700 to 5000 mg/m², 800 to5000 mg/m², 900 to 5000 mg/m², 1000 to 5000 mg/m², 1200 to 5000 mg/m²,1400 to 5000 mg/m², 1600 to 5000 mg/m², 1800 to 5000 mg/m², 2000 to 5000mg/m², 2200 to 5000 mg/m², 2400 to 5000 mg/m², 2600 to 5000 mg/m², 2800to 5000 mg/m², 3000 to 5000 mg/m², 3200 to 5000 mg/m², 3400 to 5000mg/m², 3600 to 5000 mg/m², 3800 to 5000 mg/m², 4000 to 5000 mg/m², 4200to 5000 mg/m², 4400 to 5000 mg/m², 4600 to 5000 mg/m² or 4800 to 5000mg/m², wherein the disclosure of these ranges is intended as acontinuous range including every value between the minimum and maximumvalues.

In some embodiments of the method disclosed herein, the pharmaceuticalcomposition can be configured to be administered to the subject in arange of from 300 mg to 8000 mg. In some cases, the pharmaceuticalcomposition can be administered to the subject in a range of from 300 to8000 mg, 400 to 8000 mg, 500 to 8000 mg, 600 to 8000 mg, 700 to 8000 mg,800 to 8000 mg, 900 to 8000 mg, 1000 to 8000 mg, 1200 to 8000 mg, 1400to 8000 mg, 1600 to 8000 mg, 1800 to 8000 mg, 2000 to 8000 mg, 2500 to8000 mg, 3000 to 8000 mg, 3500 to 8000 mg, 4000 to 8000 mg, 4500 to 8000mg, 5000 to 8000 mg, 5500 to 8000 mg, 6000 to 8000 mg, 6500 to 8000 mg,7000 to 8000 mg or 7500 to 8000 mg. In some cases, the pharmaceuticalcomposition can be administered to the subject in a range of from 5 to150 mg/kg, 10 to 150 mg/kg, 15 to 150 mg/kg, 20 to 150 mg/kg, 25 to 150mg/kg, 30 to 150 mg/kg, 35 to 150 mg/kg, 40 to 150 mg/kg, 45 to 150mg/kg, 50 to 150 mg/kg, 55 to 150 mg/kg, 60 to 150 mg/kg, 65 to 150mg/kg, 70 to 150 mg/kg, 75 to 150 mg/kg, 80 to 150 mg/kg, 85 to 150mg/kg, 90 to 150 mg/kg, 95 to 150 mg/kg, 100 to 150 mg/kg, 110 to 150mg/kg, 120 to 150 mg/kg, 130 to 150 mg/kg or 140 to 150 mg/kg, of thebody weight of the subject.

In some embodiments, the pharmaceutical composition can be configured tohave the modified antibody at a concentration in a range of from 10mg/mL to 150 mg/mL. In some cases, the pharmaceutical composition can beconfigured to have the modified antibody at a concentration at 10 mg/mLto 150 mg/mL, 20 mg/mL to 150 mg/mL, 30 mg/mL to 150 mg/mL, 40 mg/mL to150 mg/mL, 50 mg/mL to 150 mg/mL, 60 mg/mL to 150 mg/mL, 70 mg/mL to 150mg/mL, 80 mg/mL to 150 mg/mL, 90 mg/mL to 150 mg/mL, 100 mg/mL to 150mg/mL, 110 mg/mL to 150 mg/mL, 120 mg/mL to 150 mg/mL, 130 mg/mL to 150mg/mL or 140 mg/mL to 150 mg/mL. The concentration can be the totalprotein concentration of the antibody in the pharmaceutical composition.

In some cases of the method disclosed herein, the pharmaceuticalcomposition can be administered to the subject via intravenous injection(IV), intramuscular injection (IM), subcutaneous (SC) injection, or acombination thereof.

In some embodiments of the method disclosed herein, the effective dosagecan be determined by a dosing process that can comprise determiningconcentration progression data based on calculated or measuredpharmacokinetics (PK), testing plasma concentrations over a testingperiod of time, predicted plasma concentrations over a prediction periodof time, or a combination thereof, of the modified antibody or theantigen-binding fragment thereof, and producing the effective dosagebased on the concentration progression data. In some embodiments, theeffective dosage can be determined by predicted plasma concentrationsover a prediction period of time, wherein the predicted plasmaconcentrations can be produced by measuring actual plasma concentrationsof the modified antibody in a subject selected form a primate or a humanover a measurement period of time to produce measured concentration dataand interpolating and extrapolating the measured concentration data toproduce the predicted plasma concentrations in a selected predictionperiod of time.

In some embodiments of the method disclosed herein, the effective dosagecan be selected to maintain the plasma concentration in a range of from10 μg/mL to 1500 μg/mL in 3 to 12 months after the administration. Sucheffective dosage can be suitable for preventing the disease in a subjectfor an extended period of time, such as 3 to 12 months.

In some embodiments of the method disclosed herein, the effective dosagecan be selected to maintain the plasma concentration in a range of from1500 μg/mL to 3500 μg/mL in 1 day to 2 months after the administration.Such high effective dosage can be suitable for treating the disease fora shorter period of time, for example, from 1 day to 60 days.

In some embodiments of the method disclosed herein, the pharmaceuticalcomposition further comprises one or more subsequent modified antibodiesselected from a first subsequent modified antibody comprising twoantigen-binding domains each having same or different affinities to theSARS-CoV-2, a second subsequent modified antibody comprising a firstantigen-binding domain having a binding affinity to the SARS-CoV-2 and asecond antigen-binding domain having a binding affinity to a secondpathogen that is different from the SARS-CoV-2, a third subsequentmodified antibody comprising two antigen-binding domains each having asame or different binding affinity to the second pathogen, or acombination thereof. As mentioned above, the term “different affinitiesto the SARS-CoV-2” refers affinity that can bind to a different epitopeor binding site of the SARS-CoV-2, a different affinity level that canbind to the same epitope or binding site of the SARS-CoV-2, or acombination thereof. The binding affinity to the second pathogen can beselected from a binding affinity to SARS-CoV, MERS-CoV, one or morebacteria, one or more fungus, one or more viruses, one or moreparasites, a part thereof, or a combination thereof.

In some embodiments of the method disclosed herein can further compriseadministering a pharmaceutically effective amount of one or morebioactive agents to the subject simultaneously or sequentially with thepharmaceutical composition, wherein the bioactive agent comprises atherapeutic agent or a prophylactic agent selected from an anti-viralagent, an antiviral peptide, an anti-viral antibody, an anti-viralcompound, an anti-viral cytokine, an anti-viral oligonucleotide, an RNAdependent RNA polymerase inhibitor, a non-nucleoside reversetranscriptase inhibitor (NNRTI), nucleoside reverse transcriptaseinhibitor (NRTI), purine nucleoside, antiviral interferon, adamantineantiviral compound, remdesivir, chloroquine, hydroxychloroquine,lopinavir, ritonavir, APN01, favilavir, mesalazine, toremifene,eplerenone, paroxetine, sirolimus, dactinomycin, irbesartan, emodin,mercaptopurine, melatonin, quinacrine, carvedilol, colchicine, camphor,equilin, oxymetholone, nafamosta, camostat, baricitinib, darunavir,ribavirin, galidesivir, BCX-4430, Arbidol, nitazoxanide, one or morederivatives thereof, or any combination thereof.

In some embodiments, the antibodies or antigen-binding fragments thereofprovided herein may be administered alone or in combination atherapeutically effective amount of a second bioactive agent. The secondbioactive agent can be a therapeutic agent or a prophylactic agent.

In some embodiments, the second therapeutic agent is an anti-viralagent. In some embodiments, the anti-viral agent comprises an antiviralpeptide, an anti-viral antibody, an anti-viral compound, an anti-viralcytokine, or an anti-viral oligonucleotide. In some embodiments, theanti-viral agent is an RNA dependent RNA polymerase inhibitor, anon-nucleoside reverse transcriptase inhibitor (NNRTI), nucleosidereverse transcriptase inhibitor (NRTI), purine nucleoside, antiviralcytokines such as interferon, adamantine antiviral compound, anti-RBDantibody, anti-S1 antibody, anti-S2 antibody, siRNAs Targeting mRNA ofcoronavirus proteins M, N, or E (Chinese patent applications CN101173275and CN1648249), siRNAs targeting replicase and RNA polymerase region (USpatent application US20050004063), RNA Aptamers (Korean patentapplications KR2009128837 and KR 2012139512), ribozymes (Japanese patentapplication JP2007043942), antisense oligonucleotides (PCT patentapplication WO2005023083), or any other suitable antiviral agent. Incertain embodiments, the anti-viral compound is selected from the groupconsisting of remdesivir, chloroquine, hydroxychloroquine, lopinavir,ritonavir, APN01, favilavir, mesalazine, toremifene, eplerenone,paroxetine, sirolimus, dactinomycin, irbesartan, emodin, mercaptopurine,melatonin, quinacrine, carvedilol, colchicine, camphor, equilin,oxymetholone, nafamosta, camostat, baricitinib, darunavir, ribavirin,galidesivir, BCX-4430, Arbidol, nitazoxanide, derivatives thereof, orany combination thereof. More examples of potentially useful anti-viralagents for SARS-CoV-2 reviewed by C. Liu et al, ACS Cent. Sci. 2020, 6,3, 315-331, which is incorporate herein to its entirety.

In certain embodiments, the second bioactive agent (e.g. prophylacticagent) can be a SARS-CoV-2 vaccine (e.g. mRNA-1273 by Moderna, anAAV-based vaccine capable of expressing an SARS-CoV-2 immunogen), anantibody (e.g. directed to SARS-CoV-2), lymphokines, hematopoieticgrowth factors (such as IL-2, IL-3, IL-7, and IL-15), which can forexample serve to increase the number or activity of effector cells whichinteract with the antibodies.

In certain embodiments, the second bioactive agent can comprise hormonaltherapy, immunotherapy, and anti-inflammatory agents.

In certain of these embodiments, an antibody or antigen-binding fragmentthereof provided herein may be administered simultaneously with the oneor more additional bioactive agents, and in certain of these embodimentsthe antibody or antigen-binding fragment thereof and the additionaltherapeutic agent(s) may be administered as part of the samepharmaceutical composition. However, an antibody or antigen-bindingfragment thereof administered “in combination” with another bioactiveagent does not have to be administered simultaneously with or in thesame composition as the agent. An antibody or antigen-binding fragmentthereof administered prior to or after another agent is considered to beadministered “in combination” with that agent as the phrase is usedherein, even if the antibody or antigen-binding fragment and the secondagent are administered via different routes. Where possible, additionalbioactive agents administered in combination with the antibodies orantigen-binding fragments thereof disclosed herein are administeredaccording to the schedule listed in the product information sheet of theadditional therapeutic agent, or according to the Physicians' DeskReference 2003 (Physicians' Desk Reference, 57th Ed; Medical EconomicsCompany; ISBN: 1563634457; 57th edition (November 2002)) or protocolswell known in the art.

One advantage of the modified antibody, the pharmaceutical compositionand the method disclosed herein is that the modified antibody or anantigen-binding fragment thereof comprising at least an antigen-bindingdomain having an antigen-binding affinity and a covalently linkedmodified human IgG constant domain, wherein the modified human IgGconstant domain comprises a substitution with tyrosine at amino acidresidue 252, a substitution with threonine at amino acid residue 254,and a substitution with glutamic acid at amino acid residue 256,numbered according to the EU index as in Kabat, said modified antibodyhas an increased affinity for FcRn compared to the affinity to FcRn ofan antibody having a wild type human IgG constant domain. Such antibodycan have extended half-life in vivo. Not wishing to be bound by aparticular theory or a mechanism, Applicants believe that the increasedaffinity to FcRn can help the antibody to escape intracellulardegradations and increase the antibody recycling, therefore increasingthe amount of the antibody remaining in the blood stream of the subjectpreventing or treating the disease.

Another advantage of the modified antibody, the pharmaceuticalcomposition and the method disclosed herein is that the modifiedantibody can have a reduced affinity to human Fcγ receptors (FcγR) thatbelong to the immunoglobulin superfamily. The reduced affinity to humanFcγR can help to reduce certain immune response side effects, such asantibody-dependent enhancement (ADE).

Methods of Virus Detection

In another aspect, the present disclosure provides a method of detectingpresence or amount of SARS-CoV-2 virus antigen in a sample. In someembodiments, the SARS-CoV-2 virus antigen comprises spike protein, orcomprises the SARS-CoV-2 virus particle. In some embodiments, the methodcomprises contacting the sample with the antibody or antigen bindingfragment disclosed herein, and determining the presence or the amount ofthe SARS-CoV-2 virus antigen in the sample.

In certain embodiments, the anti-SARS-CoV-2 antibody disclosed herein isused in a method of diagnosing a subject suffering from a disorder(e.g., SARS-CoV-2 infection), the method comprising: determining thepresence or amount of SARS-CoV-2 virus antigen in a sample obtained fromthe subject by contacting the sample with an anti-SARS-CoV-2 antibody ofthe disclosure and detecting the presence of the bound antibody.

Any sample suspected of containing SARS-CoV-2 virus can be used. In someembodiments, a suitable sample can be obtained from respiratory tract ofthe subject, for example, an upper respiratory nasopharyngeal swab (NP),oropharyngeal swabs (OP), sputum, a lower respiratory tract aspirate,bronchoalveolar lavage sample, nasopharyngeal wash, nasopharyngealaspirate, nasal aspirate, a nasal swap, a throat swap, a bronchoalveolarlavage fluid (BALF), a cell or tissue sample from respiratory tract orfrom lung, and the like. In some embodiments, a suitable sample can be abody fluid sample such as a whole blood sample, a serum sample, or aplasma sample. In some embodiments, a suitable sample can be a urinesample or a stool sample.

The presence or level of SARS-CoV-2 virus antigen in a sample can bedetermined based on the detection of the presence or level of thecomplex of the virus antigen bound by the antibody or the antigenbinding fragment thereof disclosed herein. Any suitable methods can beused for such detection, for example, by immunoassays such asimmunohistochemistry (IHC), immunofluorescence (IF), immunoblotting(e.g., Western blotting), flow cytometry (e.g., FACS™), Enzyme-linkedImmunosorbant Assay (ELISA), enzyme immunoassay (ETA), andradioimmunoassay (RIA).

For a review of immunological and immunoassay procedures, see Basic andClinical Immunology (Stites & Terr eds., 7^(th) ed. 1991). Moreover, theimmunoassays can be performed in any of several configurations, whichare reviewed extensively in Enzyme Immunoassay (Maggio, ed., 1980); andHarlow & Lane, supra. For a review of the general immunoassays, see alsoMethods in Cell Biology: Antibodies in Cell Biology, volume 37 (Asai,ed. 1993); Basic and Clinical Immunology (Stites & Terr, eds., 7^(th)ed. 1991).

In certain embodiments, the antibodies or the antigen binding fragmentsthereof disclosed herein are detectably labeled, or are not labeled butcan react with a second molecule which is detectably labeled (e.g. adetectably labeled secondary antibody).

In certain embodiments, the antibodies or the antigen binding fragmentsthereof disclosed herein may be immobilized on a solid substrate. Theimmobilization can be via covalent linking or non-covalent attachment(e.g. coating). Examples of solid substrate include porous andnon-porous materials, latex particles, magnetic particles,microparticles, strips, beads, membranes, microtiter wells and plastictubes. The choice of solid phase material and method of detectablylabeling can be determined based upon desired assay format performancecharacteristics.

The level of the SARS-CoV-2 antigen can be determined, for example, bynormalizing to a control value or to a standard curve. The control valuecan be predetermined, or determined concurrently.

The assays and methods provided herein for the measurement of the levelof the SARS-CoV-2 antigen can be adapted or optimized for use inautomated and semi-automated systems, or point of care assay systems.

Methods of Antibody Detection

In another aspect, the present disclosure provides a method of detectingpresence or amount of an antibody capable of specifically binding to RBDof the spike protein of SARS-CoV-2 in a sample, comprising contactingthe sample with a polypeptide comprising an amino acid sequencecomprising SEQ ID NO: 128, and determining the presence or the level ofthe antibody in the sample. In some embodiments, the absence of theantibody in the sample or the level of the antibody in the sample beingbelow a threshold indicates that the subject is more likely to sufferfrom disease progression.

In another aspect, the present disclosure provides a method ofdetermining or predicting the likelihood of disease progression in asubject infected with SARS-CoV-2, the method comprising: contacting asample obtained from the subject with a polypeptide comprising an aminoacid sequence comprising SEQ ID NO: 128, and detecting the presence orthe level of an antibody in the sample wherein the antibody is capableof specifically binding to RBD of the spike protein of the SARS-CoV-2,wherein the subject is likely to experience disease progression when theantibody in the sample is absent or is below a threshold.

A subject infected with SARS-CoV-2 can produce antibodies against theSARS-CoV-2 antigens. Such antibodies produced by human immune system arepolyclonal, and can bind to different antigens or epitopes ofSARS-CoV-2. Without wishing to be bound by any theory, it isunexpectedly found by the inventors that the presence or level of theantibodies specific to the RBD of the spike protein of the SARS-CoV-2can be indicative of likelihood of disease progression in the subject.Antibodies capable of specifically binding to the RBD of the spikeprotein of the SARS-CoV-2 (“RBD-specific antibodies”) are found by theinventors to be capable of effectively competing with ACE2 receptor forbinding to the RBD, and also provide for SARS-CoV-2 virus neutralizingactivity. The presence of such a RBD-specific antibody can be associatedwith an effective immune response to the SARS-CoV-2, and the titer ofsuch RBD-specific antibody in the body may correlate to the prognosis ofthe SARS-CoV-2 infection or a disease, disorder or condition associatedwith SARs-CoV-2 infection.

A threshold of the level of the RBD-specific antibodies can bepredetermined. The threshold refers to a level of the RBD-specificantibodies above which the sample is scored as being positive forRBD-specific antibodies. For example, the threshold can be a level abovewhich the sample is scored as having sufficient neutralizing activityagainst the SARS-CoV-2. If the level of the RBD-specific antibodies isbelow the threshold, it could indicate insufficient protective immunityin the subject, and hence likelihood of disease progression. Incontrast, if the level of the RBD-specific antibodies in the samplereaches or is above the threshold, it could indicate protective immunityin the subject, and hence less likely to suffer from diseaseprogression.

Any sample suspected of containing antibodies can be used. In someembodiments, a suitable sample can be obtained from blood, for example,a whole blood sample, a serum sample, or a plasma sample. In someembodiments, said sample is obtained from a subject suspected of having,inflicted with, or under treatment for SARS-CoV-2 infection, or adisease, disorder or condition associated with SARs-CoV-2 infection.

Polypeptides comprising the RBD of the spike protein of SARS-CoV-2 canbe used in the methods provided to herein to detect presence or level ofthe RBD-specific antibodies in the subject. In certain embodiments, theRBD of the spike protein of SARS-CoV-2 comprises an amino acid sequencecomprising SEQ ID NO: 128. In certain embodiments, the polypeptides canfurther comprise a tag. Exemplary tag include, without limitation, 6×His tag or its fusion such SEQ ID NO: 132 or SEQ ID NO: 133. Thepolypeptides comprising RBD may be produced by recombinant methods(e.g., by prokaryotic expression system or eukaryotic expressionsystem), or chemically synthesized (e.g. by solid phase synthesis, orsolution synthesis method). Solid phase synthesis method is described byMerrifield in J.A.C.S. 85: 2149-2154 (1963) or the standard solutionsynthesis method described in “Peptide Synthesis” by Bodanszky, et al,second edition, John Wiley and Sons, 1976. The polypeptides can bepurified by methods known in the art. Various methods of proteinpurification may be employed and such methods are known in the art anddescribed for example in Deutscher, Methods in Enzymology, 182 (1990);Scopes, Protein Purification: Principles and Practice, Springer-Verlag,New York (1982). The purification step(s) selected will depend, forexample, on the nature of the production process used and the particularpolypeptide of the present application produced.

The presence or level of RBD-specific antibodies in a sample can bedetermined based on the detection of the presence or level of thecomplex of the RBD bound by the RBD-specific antibodies. Any suitablemethods can be used for such detection, for example, by immunoassayssuch as immunohistochemistry immunofluorescence (IF), immunoblotting(e.g., Western blotting), flow cytometry (e.g., FACS™), Enzyme-linkedImmunosorbant Assay (ELISA), enzyme immunoassay (EIA), andradioimmunoassay (RIA), as described above.

In certain embodiments, the polypeptide comprising RBD of the spikeprotein of the SARS-CoV-2 may be immobilized on a solid substrate. Theimmobilization can be via covalent linking or non-covalent attachment(e.g. coating). The sample suspected of containing the RBD-specificantibodies can be brought into contact with the bound polypeptide. Aftera suitable period of incubation, for a period of time sufficient toallow capture of the RBD-specific antibodies via formation ofantibody-antigen complex. After washing away any unreacted materials, adetection antibody specific to the captured antibody can be added, whichcan produce a detectable signal to allow detection of the capturedantibody. The results may either be qualitative, by simple observationof the visible signal, or may be quantitated by comparing with a controlsample containing known amounts of the detectable signal.

In another aspect, the present disclosure provides a method ofmonitoring treatment response in a subject infected with SARS-CoV-2 andreceived a treatment, the method comprising: (i) contacting a samplefrom the subject with a peptide comprising an amino acid sequencecomprising SEQ ID NO: 128; (ii) detecting a first level of an antibodyin the sample wherein the antibody is capable of specifically binding toRBD of the spike protein of the SARS-CoV-2; and (iii) comparing thefirst level of the antibody with a second level of the antibody detectedin the subject prior to the treatment; wherein the first level beinghigher than the second level indicates that the subject is responsive tothe treatment.

In one embodiment, a sample is obtained from a subject or patient priorto any treatment. In another embodiment, a test sample is obtainedduring or after treatment such as anti-viral treatment.

In one aspect, the present disclosure provides a kit for detecting anantibody capable of specifically binding to receptor-binding domain(RBD) of the spike protein of SARS-CoV-2, comprising a polypeptidecomprising an amino acid sequence comprising SEQ ID NO: 128. In someembodiments, the polypeptide is immobilized on a substrate. In someembodiments, the kit further comprises a set of reagents for detectingcomplex of the antibody bound to the polypeptide.

Kits

In certain embodiments, the present disclosure provides a kit comprisingone or more of the antibody or an antigen-binding fragment thereofprovided herein. In certain embodiments, the kit disclosed herein is atherapeutic kit. In certain embodiments, the kit disclosed herein is adiagnostic kit.

Such kits can further include, if desired, one or more of variousconventional kit components, such as, for example, containers with oneor more pharmaceutically acceptable carriers, additional containersetc., as will be readily apparent to a person skilled in the art.Instructions, either as inserts or a label, indicating quantities of thecomponents to be administered, guidelines for administration, and/orguidelines for mixing the components, can also be included in the kit.

In certain embodiments, where the antibody is labeled with an enzyme,the kit will include substrates and cofactors required by the enzyme(e.g., a substrate precursor which provides the detectable chromophoreor fluorophore). In addition, other additives may be included such asstabilizers, buffers (e.g., a block buffer or lysis buffer) and thelike. The relative amounts of the various reagents may be varied widelyto provide for concentrations in solution of the reagents whichsubstantially optimize the sensitivity of the assay. Particularly, thereagents may be provided as dry powders, usually lyophilized, includingexcipients which on dissolution will provide a reagent solution havingthe appropriate concentration.

Also provided are diagnostic or detection reagents and kits comprisingone or more such reagents for use in a variety of detection assays,including for example, immunoassays such as ELISA (sandwich-type orcompetitive format). The kit's components may be pre-attached to a solidsupport, or may be applied to the surface of a solid support when thekit is used. In some embodiments, the signal generating means may comepre-associated with an antibody of the invention or may requirecombination with one or more components, e.g., buffers, antibody-enzymeconjugates, enzyme substrates, or the like, prior to use. Kits may alsoinclude additional reagents, e.g., blocking reagents for reducingnonspecific binding to the solid phase surface, washing reagents, enzymesubstrates, and the like. The solid phase surface may be in the form ofa tube, a bead, a microtiter plate, a microsphere, or other materialssuitable for immobilizing proteins, peptides, or polypeptides. Inparticular aspects, an enzyme that catalyzes the formation of achemiluminescent or chromogenic product or the reduction of achemiluminescent or chromogenic substrate is a component of the signalgenerating means. Such enzymes are well known in the art. Kits maycomprise any of the capture agents and detection reagents describedherein. Optionally the kit may also comprise instructions for carryingout the methods of the invention.

The detection kits disclosed herein may also be prepared that compriseat least one of the antibodies or antigen-binding fragments disclosedherein and instructions for using the composition as a detectionreagent. Containers for use in such kits may typically comprise at leastone vial, test tube, flask, bottle, syringe or other suitable container,into which one or more of the detection composition(s) may be placed,and preferably suitably aliquoted. The kits disclosed herein will alsotypically include a means for containing the vial(s) in closeconfinement for commercial sale, such as, e.g., injection or blow-moldedplastic containers into which the desired vial(s) are retained. Where aradiolabel, chromogenic, fluorigenic, or other type of detectable labelor detecting means is included within the kit, the labeling agent may beprovided either in the same container as the detection compositionitself, or may alternatively be placed in a second distinct containermeans into which this second composition may be placed and suitablyaliquoted. Alternatively, the detection reagent may be prepared in asingle container means, and in most cases, the kit will also typicallyinclude a means for containing the vial(s) in close confinement forcommercial sale and/or convenient packaging and delivery.

A device or apparatus for carrying out the detection or monitoringmethods described herein is also provided. Such an apparatus may includea chamber or tube into which sample can be input, a fluid handlingsystem optionally including valves or pumps to direct flow of the samplethrough the device, optionally filters to separate plasma or serum fromblood, mixing chambers for the addition of capture agents or detectionreagents, and optionally a detection device for detecting the amount ofdetectable label bound to the capture agent immunocomplex. The flow ofsample may be passive (e.g., by capillary, hydrostatic, or other forcesthat do not require further manipulation of the device once sample isapplied) or active (e.g., by application of force generated viamechanical pumps, electroosmotic pumps, centrifugal force, or increasedair pressure), or by a combination of active and passive forces.

The following examples are provided to better illustrate the claimedinvention and are not to be interpreted as limiting the scope of theinvention. All specific compositions, materials, and methods describedbelow, in whole or in part, fall within the scope of the presentinvention. These specific compositions, materials, and methods are notintended to limit the invention, but merely to illustrate specificembodiments falling within the scope of the invention. One skilled inthe art may develop equivalent compositions, materials, and methodswithout the exercise of inventive capacity and without departing fromthe scope of the invention. It will be understood that many variationscan be made in the procedures herein described while still remainingwithin the bounds of the present invention. It is the intention of theinventors that such variations are included within the scope of theinvention.

EXAMPLE 1

Materials and Methods

Patients and blood samples. A total of eight patients aged 10 to 66years old infected with SARS-CoV-2 were enrolled (Table 5). A plasmasample from a healthy control was also included. Of these eightpatients, six (P#1 through P#4, P#8, and P#16) had exposure historythrough personal visit and two had direct contact with individuals fromexposed area. Four subjects (P#1 through P#4) were part of a familycluster (P#1 through P#5) infected and subsequently transmittedinfection to P#5 after returning to Shenzhen. All patients werehospitalized at Shenzhen Third People's Hospital, the designated cityhospital for treatment of COVID-19 infected patients, three to nine daysafter symptom onset. All patients presented with fever, fatigue, and drycough and three (P#1, P#2 and P#5) developed severe pneumonia. Fourpatients (P#1, P#2, P#5, and P#22) were 60 years or older, of whichthree (P#1, P#2, and P#22) had underlying disease such as hypertension.SARS-CoV-2 infection status was verified by RT-PCR of nasopharyngealswab and throat swab specimens. No patient had detectable influenza A,B, respiratory syncytial virus (RSV), or adenovirus co-infections. Chestcomputed tomographic scans showed varying degrees of bilateral lungpatchy shadows or opacity. All patients received interferon andribavirin and/or methylprednisolone treatments, recovered and weredischarged except for P#1, who succumbed to disease in hospital. Single(P#1, P#3, P#5, P#8, P#16, and P#22) or sequential (P#2 and P#4) bloodsamples were collected during hospitalization and follow-up visits andseparated into plasma and peripheral blood mononuclear cells (PBMCs) byFicoll-Hypaque gradient (GE Healthcare) centrifugation. All plasmasamples were heat-inactivated at 56° C. for 1 h before being stored at−80° C. PBMCs were maintained in freezing media and stored in liquidnitrogen until use.

Recombinant RBDs and trimeric Spike from SARS-CoV-2, SARS-CoV, andMERS-CoV and receptor ACE2. Recombinant RBDs and trimeric Spike forMERS-CoV, SARS-CoV, and SARS-CoV-2 and the N-terminal peptidase domainof human ACE2 (residues Ser19-Asp615) were expressed using theBac-to-Bac baculovirus system (Invitrogen) as previously described (Gui,M. et al. Cell Res 27, 119-129 (2017); Song, W. et al. PLoS Pathog 14,e1007236-e1007236 (2018); Wang, N. et al. Cell Res 23, 986-993 (2013);Jiang, L. et al. Sci Transl Med 6, 234ra259-234ra259 (2014); Zhang, S.et al. Cell Rep 24, 441-452 (2018)). Amino acid sequence for RBD ofspike protein for MERS-CoV is shown in SEQ ID NO: 126, and thepolynucleotide sequence is shown in SEQ ID NO: 127. Amino acid sequencefor extracellular domain of the spike protein for MERS-CoV is shown inSEQ ID NO: 123. Amino acid sequence for RBD of spike protein forSARS-CoV is shown in SEQ ID NO: 124, and the polynucleotide sequence isshown in SEQ ID NO: 125. Amino acid sequence for extracellular domain ofthe spike protein for SARS-CoV is shown in SEQ ID NO: 122. Amino acidsequence for RBD of spike protein for SARS-CoV-2 is shown in SEQ ID NO:128, and the polynucleotide sequence is shown in SEQ ID NO: 129. Aminoacid sequence for extracellular domain of the spike protein forSARS-CoV-2 is shown in SEQ ID NO: 121. Extracellular domains of thespike protein were fused to an artificial sequence to enable formationof a trimeric Spike structure in vitro.

SARS-CoV-2 RBD (residues Arg319-Phe541) containing the gp67 secretionsignal peptide (SEQ ID NO: 130) and a C-terminal hexahistidine tag (SEQID NO: 132) or strap tag was inserted into pFastBac-Dual vectors(Invitrogen) and transformed into DH10Bac component cells. The bacmidwas extracted and further transfected into Sf9 cells using cationiclipid Cellfectin® II Reagents (Invitrogen). The recombinant viruses wereharvested from the transfected supernatant and amplified to generatehigh-titer virus stock. Viruses were then used to infect High Five cellsfor RBD and trimeric Spike expression. Secreted RBD and trimeric Spikewere harvested from the supernatant and purified by gel filtrationchromatography as previously reported (Gui, M. et al. Cell Res 27,119-129 (2017); Song, W. et al. PLoS Pathog 14, e1007236-e1007236(2018); Wang, N. et al. Cell Res 23, 986-993 (2013); Jiang, L. et al.Sci Transl Med 6, 234ra259-234ra259 (2014); Zhang, S. et al. Cell Rep24, 441-452 (2018)).

ELISA analysis of plasma and antibody binding to RBD, trimeric Spike,and NP proteins. The recombinant RBDs and trimeric Spike derived fromSARS-CoV-2, SARS-CoV and MERS-CoV and the SARS-CoV-2 NP protein (SinoBiological, Beijing) were diluted to final concentrations of 0.5 μg/mlor 2 μg/ml, then coated onto 96-well plates and incubated at 4° C.overnight. Samples were washed with PBS-T (PBS containing 0.05% Tween20) and blocked with blocking buffer (PBS containing 5% skim milk and 2%BSA) at RT for 1 h. Either serially diluted plasma samples or isolatedmAbs were added the plates and incubated at 37° C. for 1 h. Wells werethen incubated with secondary anti-human IgG labeled with HRP (ZSGB-BIO,Beijing) and TMB substrate (Kinghawk, Beijing) and optical density (OD)was measured by a spectrophotometer at 450 nm and 630 nm. The seriallydiluted plasma from healthy individuals or mAbs against SARS-CoV,MERS-CoV or HIV-1 were used as controls.

Isolation of RBD-specific single B cells by FACS. RBD-specific single Bcells were sorted as previously described (Kong, L. et al. Immunity 44,939-950 (2016); Wu, X. et al. Science 329, 856-861 (2010)). In brief,PBMCs from infected and convalescent individuals were collected andincubated with an antibody and RBD cocktail for identification ofRBD-specific B cells. The cocktail consisted of CD19-PE-Cy7, CD3-PacificBlue, CD8-Pacific Blue, CD14-Pacific Blue, CD27-APC-H7, IgG-FITC (BDBiosciences) and the recombinant RBD-Strep or RBD-His described above.Three consecutive staining steps were conducted. The first was aLIVE/DEAD Fixable Dead Cell Stain Kit (Invitrogen) in 50 μlphosphate-buffered saline (PBS) applied at RT for 20 minutes to excludedead cells. The second utilized an antibody and RBD cocktail for anadditional 30 min at 4° C. The third staining at 4° C. for 30 mininvolved either: Streptavidin-APC (eBioscience) and/or Streptavidin-PE(BD Biosciences) to target the Strep tag of RBD, or anti-his-APC andanti-his-PE antibodies (Abcam) to target the His tag of RBD. The stainedcells were washed and resuspended in PBS before being strained through a70 μm cell mesh (BD Biosciences). RBD-specific single B cells were gatedas CD19+CD3−CD8−CD14−IgG+RBD+ and sorted into 96-well PCR platescontaining 20 μl of lysis buffer (5 μl of 5× first strand buffer, 0.5 μlof RNase out, 1.25 μl of 0.1 M DTT (Invitrogen) per well and 0.0625 μlof Igepal (Sigma). Plates were then snap-frozen on dry ice and stored at−80° C. until RT reaction.

Single B cell PCR, cloning and expression of monoclonal antibodies(mAbs). The IgG heavy and light chain variable genes were amplified bynested PCR and cloned into linear expression cassettes or expressionvectors to produce full IgG1 antibodies as previously described (Liao,H.-X. et al. J Virol Methods, 2009; Tiller, T.et al. J. Immunol Methods,2008). Specifically, all second round PCR primers containing tagsequences were used to produce the linear Ig expression cassettes byoverlapping PCR. Separate primer pairs containing the specificrestriction enzyme cutting sites (heavy chain, 5′-AgeI/3′-SalI; kappachain, 5′-AgeI/3′-BsiWI; and lambda chain, 5′-AgeI/3′-XhoI) were used toamplify the cloned PCR products. The PCR products were purified andcloned into the backbone of antibody expression vectors containing theconstant regions of human IgG1. The DNA sequence for the heavy chainconstant region of human IgG1 is set forth in SEQ ID NO: 118, and theamino acid sequence for the heavy chain constant region of human IgG1 isshown in SEQ ID NO: 115. Overlapping PCR products of paired heavy andlight chain expression cassettes were co-transfected into 293T cells(ATCC) grown in 24-well plates. Antigen-specific ELISA was used todetect the binding capacity of transfected culture supernatants toSARS-CoV-2 RBD. Monoclonal antibodies were produced by transienttransfection of 293F cells (Life Technologies) with equal amounts ofpaired heavy and light chain plasmids.

Specifically, Table 4 shows the amino acid sequences and the encodingDNA sequences for the heavy chain and light chain constant regions ofthe monoclonal antibodies including P2A-1A8, P2A-1A9, P2A-1A10, P2A-1B3,P2B-2F6, P2B-2G4, P2B-2G11, P2C-1A3, P2C- 1C8, P2C-1C10, P2C-1D5,P2C-1F11, P2B-1G5, P2B-1A1, P2C-1D7, P2B-1A10, P2B-1D9, P2B-1E4,P2B-1G1, P4A-2D9, P5A-2G7, P5A-3C8, P5A-1D2, P5A-2F11, P5A-2E1, P5A-1C8,P1A-1C10, P4A-1H6, P4B-1F4, P5A-1B6, P5A-1B8, P5A-1B9, P5A-1D1,P5A-1D10, P5A-2D11, P5A-2G9, P5A-2H3, P5A-3A1, P5A-3A6, P5A-3B4,P5A-3C12, and P22A-1D1. Antibodies P2A-1A8, P2A-1A9, P2B-2F6, P2B-2G4,P2B-2G11, P2C-1D5, P2B-1G5, P2B-1A1, P2B-1D9, P2B-1E4, P5A-2G7, P5A-1D2,P5A-2E1, P5A-1D10, P5A-2D11, P5A-2G9, P5A-2H3, P5A-3A6, and P5A-3B4 havelambda light chains, and the amino acid sequence and encoding DNAsequence for the lambda constant region are shown in SEQ ID NO: 116 andSEQ ID NO: 119, respectively. Antibodies P2A-1A10, P2A-1B3, P2C-1A3,P2C-1C8, P2C-1C10, P2C-1F11, P2C-1D7, P2B-1A10, P2B-1G1, P4A-2D9,P5A-3C8, P5A-2F11, P5A-1C8, P1A-1C10, P4A-1H6, P4B-1F4, P5A-1B6,P5A-1B8, P5A-1B9, P5A-1D1, P5A-3A1, P5A-3C12, and P22A-1D1have kappalight chains, and the amino acid sequence and the encoding DNA sequencefor the kappa constant region are shown in SEQ ID NO: 117 and SEQ ID NO:120, respectively.

Antibodies in the culture supernatant was purified by affinitychromatography using Protein A beads columns (National EngineeringResearch Center for Biotechnology, Beijing) according to themanufacturer's protocol. Concentrations were determined by BCA ProteinAssay Kits (Thermo Scientific). SARS-CoV, MERS-CoV, and HIV-1 mAbs werealso included as controls. SARS-CoV antibodies (S230 and m396)previously isolated by others (Zhu, Z. et al. Proc Natl Acad Sci USA104, 12123-12128 (2007)) were synthesized, expressed in 293T cells andpurified by protein A chromatography. MERS-CoV antibodies (Mab-GD33)were derived from previously reported (Niu, P. et al. J Infect Dis 218,1249-1260 (2018)). HIV-1 antibody VRC01 was a broadly neutralizingantibody directly isolated from a patient targeting the CD4 binding siteof envelope glycoprotein 40.

Antibody binding kinetics, epitope mapping, and competition withreceptor ACE2 measured by SPR. The binding kinetics and affinity of mAbsto SARS-CoV-2 RBD were analyzed by SPR (Biacore T200, GE Healthcare).Specifically, purified RBDs were covalently immobilized to a CM5 sensorchip via amine groups in 10mM sodium acetate buffer (pH 5.0) for a finalRU around 250. SPR assays were run at a flow rate of 30m1/min in HEPEbuffer. The sensograms were fit in a 1:1 binding model with BIAEvaluation software (GE Healthcare). For epitope mapping, two differentantibodies were sequentially injected and monitored for binding activityto determine whether the two mAbs recognized separate orclosely-situated epitopes. To determine competition with the human ACE2peptidase domain, SARS-CoV-2 RBD was immobilized to a CM5 sensor chipvia amine group for a final RU around 250. Antibodies (1 μM) wereinjected onto the chip until binding steady-state was reached. ACE2 (2μM), which was produced and purified as above, was then injected for 60seconds. Blocking efficacy was determined by comparison of responseunits with and without prior antibody incubation.

Analysis of plasma and antibody binding to cell surface expressedtrimeric Spike protein. HEK 293T cells were transfected with expressionplasmid encoding the full length spike of SARS-CoV-2, SARS-CoV orMERS-CoV and incubated at 37° C. for 36 h. The cells were removed fromthe plate using trypsin and distributed into 96 well plates for theindividual staining. Cells were washed twice with 200 μl staining buffer(PBS with 2% heated-inactivated FBS) between each of the following. Thecells were stained at room temperature for 30 minutes in 100 μl stainingbuffer with 1:100 dilutions of plasma or 20 μg/ml monoclonal antibodies.The cells were then stained with PE labeled anti-human IgG Fc secondaryantibody (Biolegend) at a 1:20 dilution in 50 μl staining buffer at roomtemperature for 30 minutes. Finally, the cells were re-suspended andanalyzed with FACS Calibur instrument (BD Biosciences, USA) and FlowJo10 software (FlowJo, USA). HEK 293T cells without transfection were alsostained as background control. S230 and m396 targeting the RBD ofSARS-CoV spike (Zhu, Z. et al. Proc Natl Acad Sci USA 104, 12123-12128(2007)) and Mab-GD33 targeting the RBD of MERS-CoV spike (Niu, P. et al.J Infect Dis 218, 1249-1260 (2018)) were used as positive primaryantibody controls, while VRC01 targeting HIV-1 env (Wu, X. et al.Science 329, 856-861 (2010)) was used as an irrelevant primary antibodycontrol.

Neutralization activity of mAbs against pseudovirus and live SARS-CoV-2.SARS-CoV-2, SARS-CoV and MERS-CoV pseudovirus were generated byco-transfection of human immunodeficiency virus backbones expressingfirefly luciferase (pNL43R-E-luciferase) and pcDNA3.1 (Invitrogen)expression vectors encoding the respective full length S proteins into293T cells (ATCC) (Wang, N. et al. Cell Res 23, 986-993 (2013); Jiang,L. et al. Sci Transl Med 6, 234ra259-234ra259 (2014); Jia, W. et al.Emerg Microbes Infect 8, 760-772 (2019); Zhang, L. et al. J Med Virol78, 1-8 (2006)). Viral supernatants were collected 48 h later. Viraltiters were measured as luciferase activity in relative light units(Bright-Glo™ Luciferase Assay Vector System, Promega Biosciences).Control envelope glycoproteins derived from human immunodeficiency virus(HIV)-1 and their corresponding pseudoviruses were produced in the samemanner. Control mAbs included VRC01 against HIV-1 40; S230 and m396against SARS-CoV (Zhu, Z. et al. Proc Natl Acad Sci USA 104, 12123-12128(2007)); and Merb-GD33 against MERS-CoV 43. Neutralization assays wereperformed by incubating pseudoviruses with serial dilutions of purifiedmAbs at 37° C. for 1 h. Huh7 cells (ATCC) (approximately 1.5×10⁴ perwell) were added in duplicate to the virus-antibody mixture.Half-maximal inhibitory concentrations (IC₅₀) of the evaluated mAbs weredetermined by luciferase activity 48 h after exposure to virus-antibodymixture using GraphPad Prism 6 (GraphPad Software Inc.), data were shownin Table 6 and Tables 7a, 7b and 7c.

Neutralization activity of mAbs against live SARS-CoV-2. SARS-CoV-2focus reduction neutralization test (FRNT) was performed in a certifiedBiosafety Level 3 laboratory. Serial dilutions of testing antibodieswere conducted, mixed with 75 μl of SARS-CoV-2 (8×103 focus formingunit/ml, FFU/ml) in 96-well microwell plates and incubated for 1 hour at37° C. Mixtures were then transferred to 96-well plates seeded with VeroE6 cells and allowed absorption for 1 hour at 37° C. Inoculums were thenremoved before adding the overlay media (100 μl MEM containing 1.6%Carboxymethylcellulose, CMC). The plates were then incubated at 37° C.for 24 hours. Cells were fixed with 4% paraformaldehyde solution for 30min, and overlays were removed. Cells were permeabilized with 0.2%nonionic surfactant Triton™ X-100 and incubated with cross-reactiverabbit anti-SARS-CoV-N IgG (Sino Biological, Inc) for 1 hour at roomtemperature before adding HRP-conjugated goat anti-rabbit IgG(H+L)antibody (Jackson ImmunoResearch). Cells were further incubated at roomtemperature. The reactions were developed with KPL TrueBlue Peroxidasesubstrates (Seracare Life Sciences Inc). The numbers of SARS-CoV-2 fociwere calculated using an EliSpot reader (Cellular Technology Ltd).

Gene family usage and phylogenetic analysis of mAbs. The programIMGT/V-QUEST (http://www.imgt.org/IMGT_vquest/vquest) was used toanalyze germline gene, germline divergence or degree of somatichypermutation (SHM), the framework region (FR) and the loop length ofthe complementarity determining region 3 (CDR3) for each antibody clone.The IgG heavy and light chain variable genes were aligned using ClustalW in the BioEdit sequence analysis package(https://bioedit.software.informer.com/7.2/). Phylogenetic analyses wereperformed by the Maximum Likelihood method using MEGA X (MolecularEvolutionary Genetics Analysis across computing platforms). Severalforms of the phylogenetic trees are presented for clarity, data wereshown in Table 9a, Table 9b, FIG. 4U and FIG. 4V.

Antibody production. The production of antibodies was conducted aspreviously described (Jiang, L. et al. Sci Transl Med 6,234ra259-234ra259 (2014); Zhang, Q. et al. Sci Rep 6, 25856-25856(2016)). The genes encoding the heavy and light chains of isolatedantibodies were separately cloned into expression vectors containingIgG1 constant regions and the vectors were transiently transfected intoHEK293T or 293F cells using polyethylenimine (PEI) (Sigma). After 72 h,the antibodies secreted into the supernatant were collected and capturedby protein A SEPHAROSE™ (GE Healthcare). The bound antibodies wereeluted and further purified by gel-filtration chromatography using aSUPERDEX™ 200 High Performance column (GE Healthcare). The purifiedantibodies were either used in binding or neutralizing assays.

Crystallization and data collection. The SARS-CoV-2 RBD was mixed withthe Fab fragment of P2B-2F6, P5A-1D2, P5A-3C8 or P22A-1D1 respectivelyat a molar ratio of 1:1.2, incubated for 2 h at 4° C. and furtherpurified by gel-filtration chromatography. The purified complexconcentrated to approximately 10 mg/mL in HBS buffer (10 mM HEPES, pH7.2, 150 mM NaCl) was used for crystallization. The screening trialswere performed at 18° C. using the sitting-drop vapor-diffusion methodby mixing 0.2 μL of protein with 0.2 μL of reservoir solution. Crystalswere successfully obtained in 0.2 M magnesium formate dihydrate, 0.1Msodium acetate trihydrate, pH 4.0, 18% PEG5000mme. The purifiedcomplexes of SARS-CoV-2 RBD and the Fab fragment of P2C-1F11, P5A-1D2,P5A-3C8 or P22A-1D1 respectively were obtained using a similar process.Crystals were successfully obtained in 0.2 M magnesium formatedihydrate, 0.1M sodium acetate trihydrate, pH 4.0, 18% PEG5000mme forP2C-1F11; in 0.2M Magnesium chloride hexahydrate, 0.1Mtris(hydroxymethyl)aminomethane buffer (Tris), pH 8.5, 3.4M1,6-Hexanediol for P5A-1D2; in 0.2M Lithium sulfate monohydrate, 0.1MHEPES, pH 7.5, 25% w/v PEG 3350 for P5A-3C8; and in 0.1M potassiumchloride, 0.1M NaHEPES, pH 7.0, 15% PEG 5000MME for P22A-1D1,respectively. Crystals were harvested, soaked briefly in mother liquidwith 20% glycerol, and flash-frozen in liquid nitrogen. Diffraction datawas collected at 100 K and at a wavelength of 0.97918 Å on the BL17Ubeam line of the Shanghai Synchrotron Research Facility (SSRF).Diffraction data was auto-processed with aquarium pipeline and the dataprocessing statistics are listed in Table 10a and Table 10b and Table10c. (McCoy, A. J. et al. Journal of applied crystallography 40,658-674, (2007)).

Structural determination and refinement. The structure was determined bythe molecular replacement method with PHASER in CCP4 suite (Cohen, S. X.et al. Acta crystallographica. Section D, Biological crystallography 64,49-60, (2008)). The search models were the SARS-CoV-2 RBD structure (PDBID: 6M0J) and the structures of the variable domain of the heavy andlight chains available in the PDB with the highest sequence identities.Subsequent model building and refinement were performed using COOT andPHENIX, respectively (Emsley, P. & Cowtan, K. Acta crystallographica.Section D, Biological crystallography 60, 2126-2132, (2004); Adams, P.D. et al. Acta crystallographica. Section D, Biological crystallography58, 1948-1954, (2002)). Final Ramachandran statistics: 90.02% favoured,8.24% allowed and 1.74% outliers for the final RBD-P2C-1F11 complexstructure. Final Ramachandran statistics: 95% favoured, 3.9% allowed and0.81% outliers for the final RBD-P22A-1D1 complex structure; FinalRamachandran statistics: 94.23% favoured, 5.44% allowed and 0.32%outliers for the final RBD-P5A-1D2 complex structure; Final Ramachandranstatistics: 97% favoured, 3.1% allowed and 0.33% outliers for the finalRBD-P5A-3C8 complex structure. The structural refinement statistics arelisted in Table 10a and Table 10b. All structural figures were generatedusing PyMOL (Janson, G., Zhang, C., Prado, M. G. & Paiardini, A.Bioinformatics (Oxford, England) 33, 444-446, (2017)).

Analysis of antibody binding to cell surface expressed wild-type andmutant Spike protein. Single Alanine mutations were conducted withQuickChange Site-directed mutagenesis Kit (Agilent 210518) followed themanufacturer's instructions. HEK 293T cells were transfected withexpression plasmid encoding either wild-type or mutant full-lengthSARS-Cov-2 and incubated at 37° C. for 36 h. The cells were removed fromthe plate using trypsin and distributed into 96 well plates for theindividual staining. Cells were kept at 4° C. or on ice in the followingincubation or wash steps. Cells were washed twice with 200 μL ice-coldstaining buffer (PBS with 2% heated-inactivated FBS) between each of thefollowing. The cells were stained for 1 h in 100 μL staining buffer with10 ug/mL ACE2 protein or 2 μg/mL monoclonal antibodies. The cells werethen stained with one of the following secondary antibodies: anti-his PE(Miltyni 130120787) for ACE2, anti-human IgG Fc PE (Biolegend 410718)for nAbs, or anti-mouse IgG Fc FTIC (ThermoFisher A10673) for S2 mAb (MP08720401). Finally, the cells were re-suspended and analyzed with FACSCalibur instrument (BD Biosciences, USA) and FlowJo 10 software (FlowJo,USA). HEK 293T cells without mock transfection were stained asbackground control.

EXAMPLE 2

This example illustrates the identification of human plasma and B cellthat responses specific to SARS-CoV-2 RBD.

Cross-sectional and longitudinal blood samples from eightSARS-CoV-2-infected and convalescent subjects were collected during theearly outbreak in Shenzhen (see Table 5). Samples were named by patientnumber and either A, B, or C depending on collection sequence. Sixpatients (P#1 through P#4, P#8, and P#16) had travel history to exposedarea and the remaining two (P#5 and P#22) had direct contact with thosefrom exposed area. P#1 through P#5 is a family cluster with the firstdocumented case of human-to-human transmission of SARS-CoV-2 inShenzhen. All subjects recovered and were discharged from the hospitalexcept for P#1 who succumbed to disease despite intensive intervention.To analyze antibody binding, serial plasma dilutions were applied toenzyme-linked immunosorbent assay (ELISA) plates coated with eitherrecombinant RBD or trimeric Spike derived from SARS-CoV-2, SARS-CoV, andMERS-CoV or recombinant NP from SARS-CoV-2. Binding activity wasvisualized using anti-human IgG secondary antibodies at an opticaldensity (OD) of 450 nm. Varying degrees of binding were found acrossindividuals and among samples from the same individual. Samples fromP#1, P#2, P#5, and P#16 demonstrated higher binding to both SARS-CoV-2RBD and NP than the rest (FIG. 1A). Three sequential plasma samplescollected from P#2 over nine days during early infection showed similarbinding to SARS-CoV-2 RBD and NP and remained relative stable over thecourse of the infection. Surprisingly, virtually no cross-reactivitybetween SARS-CoV RBD and MERS-CoV RBD was detected (FIG. 1A), despitestrong recognition by the positive control antibodies. However, strongcross-reactivity was detected against trimeric Spikes from SARS-CoV andMERS-CoV in both ELISA (FIG. 1B) and cell-surface staining (FIG. 6A-FIG.6C). All samples except P#4A demonstrated significant levels ofcross-binding to SARS-CoV trimeric Spike while only those from P#1, P#2and P#4B cross recognized MERS-CoV trimeric Spike (FIG. 1B). None of theplasma samples were reactive to HIV-1 envelope trimer derived fromstrain BG505 (Sanders, R. W. et al. J Virol 76, 8875-8889, (2002)). Thesame plasma samples were also evaluated for neutralization ofpseudoviruses bearing the Spike proteins of either SARS-CoV-2, SARS-CoV,or MERS-CoV. Consistent with the antibody binding results, varyingdegrees of neutralizing activities against SARS-CoV-2 were found acrossindividuals (FIG. 1C). However, cross-neutralizing against SARS-CoV andMERS-CoV is rather minimal as all plasma samples tested, includinghealthy control plasma, had negligible levels of neutralization (FIG.1C). No detectable neutralization was found for any plasma sampleagainst the pseudovirus control bearing the HIV-1 envelope MG04 (FIG.1C). Taken together, these results suggest that RBDs from SARS-CoV-2,SARS-CoV, and MERS-CoV are likely to be immunologically distinct despitesubstantial sequence and structural similarities. Thus, regions beyondRBDs likely contribute to the observed cross-reactivity against SARS-CoVand MERS-CoV Spike protein.

Flow cytometry with a range of gating strategies was used to studySARS-CoV-2-specific B cell responses and identity B cells recognizingfluorescent-labeled RBD probes (FIG. 1D and FIG. 7A-FIG. 7K). As shownin FIG. 1E-FIG. 1F, the RBD-specific B cells constitute about0.005-0.065% among the total B cell population and 0.023-0.329% amongthe memory subpopulations. The number of RBD-specific B cells arerelatively higher in P#2, P#5, P#16, and P#22 (FIG. 1E-FIG. 1F), whichappeared to correlate well with binding activity of corresponding plasmasamples to SARS-CoV-2 RBD and trimeric Spike protein (FIG. 1A and FIG.1B). However, sample P#1A demonstrated the lowest RBD-specific B cellresponse despite high-level plasma binding. As P#1 was the only patientsuccumb to disease, it is possible that this dichotomy of high plasmabinding activity and low levels of RBD-specific B cells is a surrogatemarker of rapid disease progression.

EXAMPLE 3

This example illustrates the cloning and analysis of single B cellantibody against SARS-CoV-2 RBD.

The RBD-binding B cells identified in EXAMPLE 2 were isolated intosingle cell suspension for cloning and evaluation of the mAb response(FIG. 1D and FIG. 7A-FIG. 7K). Immunoglobulin heavy and light chainswere amplified by RT-PCR using nested primers. The amplified productswere cloned into linear expression cassettes to produce full IgG1antibodies as previously described (Kong, L. et al. Immunity 44, 939-950(2016); Liao, H.-X. et al. J Virol Methods 158, 171-179). The number ofB cell clones varied from 10 to 10⁶ among the subjects (FIG. 8).Individual IgGs were produced by transfection of linear expressioncassettes and tested for SARS-CoV-2 RBD reactivity by ELISA. On average,fifty-eight percent of the antibody clones were reactive, although greatvariability was found among different individuals (FIG. 8). Out of 358antibodies, 206 antibodies were found to specifically bind to SARS-CoV-2RBD, and by B cell cloning and sequencing, 165 distinct sequences wereobtained (Table 9). These 206 antibodies demonstrated significantdifferences in binding activity. For example, a large number ofantibodies from samples P#2B, P#2C, P#4A, P4#B, P#5A, P#16A, and P#22Ahad OD 450 values well over 4.0, while none of those from sample P#1Aexceeded 4.0. There were too few antibodies from P#3A and P#8A to makemeaningful evaluations (FIG. 8). Furthermore, samples from differentstudy subjects also demonstrated substantial differences in heavy chainvariable gene (VH) usage (FIG. 2). For instance, P#1 samples aredominated by VH3-53, 3-13, and 1-69 which constituted approximately21.4%, 14.3%, and 14.3% of the entire VH repertoire, respectively.Samples from P#2 and P#5 are more diverse in distribution and frequencyof their VH usage. However, no single or group of VH families stood outamong study subjects, suggesting patients have immunologically distinctresponses to SARS-CoV-2 infection. This hypothesis is supported by thephylogenetic analysis of all 206 VH sequences superimposed with theircorresponding binding activities as presented in FIG. 2B. Thehigh-binding clusters (80% of clusters with OD 450>3) were widelydistributed across multiple heavy chain families. In fact, majority ofthe high-binding antibodies were derived by clonal expansion of specificVH families in P#2, P#4, and P#5. Similarly, the middle- (60-80% ofclusters with OD 450>3) and low- (<60% cluster with OD 450>3) bindingclusters were also widely distributed and each consisted ofdisproportionally represented VH gene families.

As P#2 showed a large number of RBD-binding antibodies and was the onlypatient with three sequential blood samples, more detailedcharacterization of P#2 antibodies were conducted. Among a total of 69antibodies from P#2, the majority (59%) were scattered across variousbranches and the remaining (41%) were clonally expanded into three majorclusters (FIG. 3A). Antibodies from the three time points (A, B, C) donot appear to group together but rather interdigitate among themselves,suggesting they are highly related during early infection. Three cloneswere significantly enriched and each constituted between 12-14% of theentire tested repertoire (FIG. 3A). Their heavy-chain variable regionsbelong to the VH1-2*06, VH3-48*02, and VH3-9*01 families. Thecorresponding light-chain kappa (lgk) belongs to 2-40*01/2D-40*01,3-20*01, and light-chain lambda (lgl) to 2-14*02 with the respectivejoining segment kappa 4 (Jk4), Jk5 and joining segment lambda 1 (J11)(Table 9). More importantly, these clonally expanded antibodies wereidentified in all three samples indicating that they are stronglyselected for during infection. When comparing their representationwithin each cluster, VH1-2*06 and VH3-9*01 appeared to increase fromapproximately 33 to 45%, whereas VH3-48*02 decreased from 33 to 9% overthe three time points, although the number of clones was too small forstatistical significance. Interestingly, the somatic hypermutation (SHM)or germline divergence for VH1-2*06 was 0% and this cluster persistedduring the study period. However, the SHM for VH3-48*02 reached as highas 9.6% and for VH3-9*01 reached 3.8% compared to the overall average of2.2%±3.3% among the 69 VH sequences. Furthermore, the CDR3 length forVH1-2*06, VH3-48*02, and VH3-9*01 was 19aa, 16aa, and 23aa,respectively, compared with the overall average of 16±4aa among the 69VH sequences. Close examination of the longest CDR3 from the VH3-9*01cluster revealed richness in tyrosine, indicating potential hydrogenbonding and hydrophobic interactions with the surrounding residues.These results shed light on the clonal expansion and broad diversity ofRBD-specific antibodies during early infection and their potential rolein controlling SARS-CoV-2 infection.

Furthermore, we also conducted a genomic analysis and compared the heavychain variable gene (VH) and kappa or lambda light chain variable(VK/VL) genes usage in the 13 mAbs (P22A-1D1, P5A-1B9, P5A-2G7, P5A-2G9,P5A-1D1, P5A-1B8, P5A-1D2, P5A-3B4, P5A-3C8, P5A-3C12, P2C-1F11, P2B-2F6and P2B-1A10) with lowest IC₅₀ identified in the pesudovirusneutralizing analysis in Example 6. Of these 13 mAbs, 7 were found touse IGHV3-53/3-66 and paired predominantly with IGK1-9*01 (Table 9b).Four of the seven were derived from P#5 (P5A-1D1, P5A-1B8, P5A-1D2, andP5A-3C8) whereas two from P#2 (P2C-1F11 and P2B-1A10) and one from P#22(P22A-1D1). Such high prevalence (53.8%) and from diverse individualsamong the top neutralizers indicated that IGHV3-53/3-66 represented onemajor and public antibody responses against SARS-CoV-2 (FIG. 3B-FIG.3E). This finding is consistent with recent reports have also recognizeddisproportionally high prevalence of IGHV3-53/3-66 among SARS-CoV-2patients (Barnes et al., 2020; Yuan et al., 2020). Furthermore, the CDR3length of the antibodies varied from 9 to 15, located in the shorterrange among the total 165 RBD-specific antibodies identified (FIG. 3F).Their somatic hypermutation (SHM) were generally low and some reached 0%for heavy chain (P22A-1D1) or light chain (P5A-1B8 and P2C-1F11).

EXAMPLE 4

The present invention is further defined in the following Examples. Itshould be understood that these Examples, while indicating preferredembodiments of the invention, are given by way of illustration only.From the above discussion and these Examples, one skilled in the art canascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various uses andconditions.

This example illustrates the binding properties of the antibodiesagainst SARS-CoV-2 RBD.

Based on their representation and distribution on the phylogenetic tree,13 of the 69 P#2 antibodies sequences were selected for further analysis(FIG. 3A, starred). Five P#1A antibody clones were used as controls.Surface plasmon resonance (SPR) with SARS-CoV-2 RBD showed that P#2antibodies had dissociation constants (Kd) ranging from 1.38 to 21.29 nMwhile those from P#1 ranged from 8.48 to 260.50 nM or not detectable atall (FIG. 4U and FIG. 9A-FIG. 9B). SHM did not appear to correlate withKd; some germline clones with 0% divergence in both VH and VL genes(P2A-1A10, P2B-2G4, P2C-1A3, and P2C-1E1) had Kd values ranging from2.47 to 21.19 nM, which comparable to that (1.38 to 17.57 nM) of cloneswith higher levels of SHM (FIG. 4U). The Kd of representative clones(P2A-1A8, P2A-1A10, and P2A-1B3) from the three clonally expandedclusters span from 4.65 to 8.91 nM, suggesting that their expansion maynot be driven by affinity maturation. Antibody P2B-1G5 was also testedfor RBD binding, and the Kd value was 0.1 nM (Table 7a). Next, eachantibody for competition with ACE2 for binding to the SARS-CoV-2 RBDwere measured (FIG. 4B, FIG. 4U, FIG. 4V and FIG. 10A-FIG. 10B).Specifically, the RBD was covalently immobilized on a CMS sensor chipand first saturated by antibody and then flowed through with solubleACE2. Competing capacity of each antibody was measured as percentreduction in ACE2 binding with the RBD. As shown in (FIG. 4U, FIG. 10A,FIG. 10B), the evaluated antibodies demonstrated various competingcapacity with ACE2. The most powerful was P2C-1F11. Two of the threerepresentative antibodies from the clonal expanded clusters (P2A-1A10and P2A-1B3) had also strong reduction. The third representative(P2A-1A8) only showed mild reduction. Many antibodies had only limitedcompeting power with ACE2 despite impressive Kd values, suggestingbinding affinity is not predictive of ACE2 competing capacity. AntibodyP2B-1G5 was also tested for ACE2 competition, and showed 17.54%competition with ACE2 (Table 7a). Control antibodies from P#1demonstrated even lower competing power with ACE2. Surprisingly, none ofthe antibodies tested demonstrated cross-binding with SARS-CoV andMERS-CoV RBD except P1A-1C7 (Kd=4.85 μM), for which only limited crossreactivity with SARS-CoV RBD was detected (FIG. 9A-FIG. 9F).

An additional set of 13 neutralizing antibodies were also identified(see Example 5) These neutralizing antibodies demonstrated high yetvarying binding affinity to the SARS-CoV-2 RBD measured by surfaceplasmon resonance (SPR) (FIG. 9G and Table 9b). Most interestingly, ofthe top 13 neutralizing antibodies, 7 were found to use IGHV3-53/3-66and paired predominantly with IGK1-9*01 (Table 9b). Four of the sevenwere derived from P#5 (P5A-1D1, P5A-1B8, P5A-1D2, and P5A-3C8) whereastwo from P#2 (P2C-1F11 and P2B-1A10) and one from P#22 (P22A-1D1) (FIG.3D-3E). Such high prevalence (53.8%) and from diverse individuals amongthe top neutralizers indicated that IGHV3-53/3-66 represented one majorand public antibody responses against SARS-CoV-2. Furthermore, theirCDR3 length varied from 9 to 15, located in the shorter range among thetotal 165 RBD-specific antibodies identified (FIG. 3F). Their somatichypermutation (SHM) were generally low and some reached 0% for heavychain (P22A-1D1) or light chain (P5A-1B8 and P2C-1F11). Recent reportshave also recognized disproportionally high prevalence of IGHV3-53/3-66among SARS-CoV-2 patients (Barnes et al., 2020; Yuan et al., 2020).

These 13 mAbs demonstrated high yet varying binding affinity to theSARS-CoV-2 RBD measured by surface plasmon resonance (SPR) (FIG. 10C andTable 9b). All except P2B-1A10 displayed single digit or less nanomolarbinding affinity. Apart from P5A-3B4, these mAbs shared strongcompetitive capacity with ACE2 in binding to SARS-CoV-2 RBD, suggestingtheir potential mechanism of neutralization (FIG. 10C and Table 9b).

EXAMPLE 5

This example illustrates the neutralizing properties of the antibodiesagainst pseudoviruses bearing the Spike protein of SARS-CoV-2.

For a first set of antibodies P2A-1A8, P2A-1A9, P2A-1A10, P2A-1B3,P2B-2F6, P2B-2G4, P2B-2G11, P2C-1A3, P2C-1C8, P2C-1C10, P2C-1D5, andP2C-1F11, RBD binding and pseudoviruses neutralizing activities weretested. Consistent with the competing capacity findings, neutralizingactivity varied considerably with IC₅₀ values ranging from 0.03 to >50μg/ml (FIG. 4C-FIG. 4M). Within this first set of antibodies, P2C-1F11,P2B-2F6 and P2C-1A3 were the most potent with IC₅₀ 0.03, 0.05, and 0.63μg/ml, respectively. Overall, ACE2 competing capacity correlated wellwith the neutralizing activities, although this correlation was notexact in some instances. Notably, no cross-neutralization was foundeither against pseudoviruses bearing the full length Spike of SARS-CoVor MERS-CoV or with cell-surface staining of trimeric SARS-CoV andMERS-CoV Spike (FIG. 11A-FIG. 11B).

Antibody P2B-1G5 was also tested for pseudoviruses neutralizingactivities, with an IC₅₀ value of 0.11 μg/ml. The results are shown inTable 7a.

Pseudoviruses neutralizing activities were further tested using a secondset of antibodies P5A-2G7, P5A-3C8, P5A-1D2, P2B-1G1, P5A-1C8, P5A-2F11,P5A-2E1, P2B-1A1, P2C-1D7, P2B-1A10, P2B-1D9, P2B-1E4, and P4A-2D9.Results showed that most of these antibodies were potent, and IC₅₀ wasfound below 1 μg/ml for antibodies P2B-1G5, P5A-2G7, P5A-3C8, P5A-1D2,P5A-1C8, P5A-2F11, P2B-1A1, P2C-1D7, and P2B-1A10 (Table 7b).

Pseudoviruses neutralizing activities were also tested using a third setof antibodies P1A-1C10, P4A-1H6, P4B-1F4, P5A-1B6, P5A-1B8, P5A-1B9,P5A-1D1, P5A-1D10, P5A- 2D11, P5A-2G9, P5A-2H3, P5A-3A1, P5A-3A6,P5A-3B4, P5A-3C12, and P22A-1D1. Results showed that most of theseantibodies were potent, and IC₅₀ was found below 1 μg/ml for antibodiesP4A-1H6, P5A-1B6, P5A-1B8, P5A-1B9, P5A-1D1, P5A-1D10, P5A-2D11,P5A-2G9, P5A-2H3, P5A-3A1, P5A-3A6, P5A-3B4, P5A-3C12, and P22A-1D1(Table 7c and FIG. 4V). Among them, P5A-1B9, P22A-1D1, P5A-1D1, P5A-1B8,P5A-2G9, P5A-3B4 and P5A-3C12 were the most potent with IC₅₀ lower than0.1 μg/ml (0.0014, 0.0038, 0.0096, 0.0115, 0.0158, 0.0993 and 0.0996μg/ml, respectively).

By summarizing the initial screening result by using pseudovirus, weidentified 13 mAbs (P22A-1D1, P5A-1B9, P5A-2G7, P5A-2G9, P5A-1D1,P5A-1B8, P5A-1D2, P5A-3B4, P5A-3C8, P5A-3C12, P2C-1F11, P2B-2F6 andP2B-1A10) with IC₅₀ ranging from 0.0014 μg/mL to 0.0996 μg/mL (FIG. 4Nthrough FIG. 4R). The IC₅₀ of remaining antibodies, however, spansbetween 0.1 μg/mL and 50 μg/mL or higher (Table 7d).

We selected the top seven potent neutralizing antibodies againstpseudovirus in the first set of antibodies to analyze their inhibitoryactivities against live SARS-CoV-2 using focus reduction neutralizationtest (FRNT) (FIG. 4S) and FIG. 12A-FIG. 12D). Consistent with theirrespective pseudovirus assay findings, P2C-1F11, P2B-2F6 and P2C-1A3demonstrated the most potent neutralization activity with IC₅₀ 0.030.41, and 0.28 μg/ml, respectively (FIG. 4U). The remaining antibodiesdemonstrated moderate neutralizing activities with IC₅₀ ranging from1.64 to 35.87 μg/ml (FIG. 4U). The further identified top 13neutralizing antibodies also demonstrated strong inhibitory activityagainst live SARS-CoV-2 based on focus reduction neutralization tests(FRNT) (FIG. 4T). For instance, the IC₅₀ for the best antibody P5A-1B9reached as low as 0.0043 μg/mL and the IC₈₀ 0.0441 μg/mL, at least10-fold more potent than those tested in the first set (FIG. 4V).

To determine whether these antibodies compete for similar epitopes onthe SARS-CoV-2 RBD, a total of six antibodies with relative strong ACE2competitive capacities and neutralization potency and analyzed in apairwise competition fashion using SPR. As shown in Table 8 and FIG. 13,variable degrees of competition were found among the pairs ofantibodies. P2C-1A3, for instance, was competitive against allantibodies tested with strong reduction capacity (FIG. 13). P2C-1F11, onthe other hand, was less competitive with other antibodies and inparticular, only minimally competitive with P2C-1C10. P2B-2F6, anotherpotent neutralizing antibody, was broadly competitive with allantibodies tested. These results indicate that the antibodies analyzedrecognized both overlapping and distinct epitopes. Different mAbs maytherefore exert their neutralizing activity through differentmechanisms.

Antibody P2B-1G5 was also analyzed in a pairwise competition fashionwith P2C-1F11 using SPR. Results was shown in Table 7a, which suggestedthat P2B-1G5 is only minimally competitive with P2C-1F11.

EXAMPLE 6

This example illustrates the structural basis for antibodyneutralization.

The crystal structure of the top three most potent neutralizingantibodies in the first set of antibodies (P2C-1F11, P2B-2F6 andP2C-1A3) was determined. Of which, P2B-2F6 Fab and P2C-1F11 Fab bound tothe SARS-CoV-2 RBD were able to form crystals and the structures ofwhich were resolved at a resolution of 2.85 angstrom (FIG. 5A and FIG.5F).

Antibody 2F6 mainly uses the heavy chain for interactions with the RBD,and the paratope region consists of 14 residues from the heavy chain(Y27, S28, S30, S31 and Y33 of HCDR1; H54 of HCDR2; G102, I103, V105,V106 and P107 of HCDR3) and 3 residues from the light chain (G31, Y32and N33 of LCDR1) (FIG. 5E). The buried surface area on the RBD is 534A² and the recognized epitope residues are all from the receptor-bindingmotif (RBM) of the RBD, including residues K444, G446, G447, N448, Y449,N450, L452, V483, E484, G485, F490 and S494 (FIG. 5E). SARS-CoV-2recognition by 2F6 is largely driven by hydrophobic interactions aroundRBD residues Y449, L452 and F490 (FIG. 5B). Structural superimpositionof the RBD-2F6 and RBD-ACE2 crystal structures indicated that thebinding of 2F6 would clash with ACE2 (FIG. 5C). The clash would happenbetween the P2B-2F6 light chain (residues R56, S58, G59, R63, S78, G79)and the ACE2 (residues D67, K68, A71, K74, E110, K114). The overlappingresidues recognized by 2F6 and ACE2 only include G446 and Y449, largelydue to their difference in angles when they approach RBD. However, thehigh affinity binding of 2F6 to the RBD (5.14 nM), which is comparableto the binding affinity between RBD and ACE2 (4.70 nM), is expected topreclude the receptor ACE2 engagement, further supported by the highACE2 competition efficiency of 2F6 in the SPR analysis (98.80% in FIG.4O), second column). We also superimposed the RBD-2F6 crystal structureonto the cryo-EM structure of the SARS-COV-2 spike trimer, in which theRBD has two different “up” and “down” conformations. Unlike the ACE2that only binds the “up” RBD, the 2F6 Fab is able bind to the RBD inboth “up” and “down” conformations without clashing with two othermonomers in the spike trimer (FIG. 5D). Therefore, we suggest thatstructural basis for 2F6 neutralization relies on directly competitionwith receptor ACE2 on spike binding.

Antibody 1F11 mainly uses the heavy chain for interactions with the RBD,and the paratope region consists of 17 residues from the heavy chain(G26, I27, T28, S31, N32 and Y33 of HCDR1; Y52, S53, G54, and S56 ofHCDR2; Y58 of HFR3; R97, L99, V100, V101, Y102 and D105 of HCDR3) and 4residues from the light chain (12 from the LFR1; S28, S30 and Y33 ofLCDR1) (FIG. 5G). The buried surface area on the RBD is shown in FIG. 5Gand the recognized 23 epitope residues are located in the RBM (Y453,L455, F456, R457, K458, S459, N460, Y473, A475, G476, 5477, F486, N487,Y489, Q493, G502 and Y505) and the core (R403, T415, G416, K417, D420and Y421) of the SARS-CoV-2 RBD (FIG. 5G). A network of hydrogen-bondinginteractions (18 between heavy chain and RBD and 2 between light chainand RBD) dominates in the recognition of SARS-CoV-2 by 1F11.

The crystal structures of P22A-1D1, P5A-3C8, and P5A-1D2 complexed withSARS-CoV-2 RBD (FIG. 5H and Table 10c) were also determined at aresolution of 2.40 Å, 2.36 Å, and 2.60 Å respectively. Antibody P2C-1F11(2.96 Å) was used it for head to head comparison. As shown in FIGS. 5H,5I, 5J, and 5K, these four antibodies (P22A-1D1, P5A-3C8, P5A-1D2 andP2C-1F11) bound to the RBD with a nearly identical angle of approach.The estimated clash volume with ACE2 was about ˜20,000 Å³ (FIG. 5H),consistent with biochemical data showing strong capacities to competewith ACE2 in binding to SARS-CoV-2 RBD (Table 9b). The heavy chains ofantibodies P22A-1D1, P5A-3C8, P5A-1D2 and P2C-1F11 share similar buriedsurfaces on the RBD. The estimated areas are 726 Å² for P22A-1D1, 668 Å²for P5A-3C8, 823 Å² for P5A-1D2 and 725 Å² for P2C-1F11 (FIG. 5I). Incontrast, the buried surface areas of the light chain are ratherdifferent. P22A-1D1 (413 Å²) and P5A-3C8 (480 Å²) are significantlylarger than P5A-1D2 (152 Å²) and P2C-1F11 (230 Å²) (FIG. 5I). The largerburied areas are translated into more epitope residues. For instance,P22A-1D1 and P5A-3C8 have 28 and 31 epitope residues on the RBD whereasP5A-1D2 and P2C-1F11 have 22 and 23, respectively (FIG. 5S).Furthermore, the epitopes of these antibodies significantly overlap withthe ACE2 binding residues on RBD. Out of 17 ACE2-binding residues onRBD, P22A-1D1 shared by 15, P5A-3C8 by 16, P5A-1D2 by 10, and P2C-1F11by 11 (FIG. 5L). The similar angles of approach to and the large overlapin binding residues on the RBD suggest that these four public antibodiesresemble ACE2 in binding to SARS-CoV-2. The coordinates and structurefactor files for the P5A-1D2, P5A-3C8 and P22A-1D1/SARS-CoV-2 RBDcomplexes have been deposited in the Protein Data Bank (PDB) underaccession numbers 7CHO, 7CHP, 7CHS, respectively.

As described in Example 3, the four antibodies P22A-1D1, P5A-3C8,P5A-1D2 and P2C-1F11 were all found to use IGHV3-53 or IGHV3-66 (Table9b). The IGHV3-53 and IGHV3-66 share the identical germline amino acidsequence except one residue. It is therefore expected that the fourantibodies shared their binding features to RBD primarily throughresidues in the heavy chain. As shown in FIG. 5M, all three HCDRs areinvolved in the binding of these four antibodies to the RBD. Heavy chainsequence alignments showed that the HCDR1 and HCDR2 are highlyconserved, whereas the HCDR3 are rather different (FIG. 5P-FIG. 5S). Ofnote, P5A-1D2 has a longer HCDR3 (15 residues) than the rest threeantibodies (11 residues).

Antibody P22A-1D1 mainly uses the heavy chain for interactions with theRBD, and the paratope region consists of 17 residues from the heavychain (G26, F27, T28, S31, N32, Y33, H52, S53, G54, S56, Y58, R97, R99,D100, Y101, Y102 and D105) and 10 residues from the light chain (Q27,G28, 129, S30, Y32, S67, H90, L91, N92 and Y94) (FIG. 5T). The buriedsurface area on the RBD is shown in FIG. 5T and the recognized 18epitope residues are located in the SARS-CoV-2 RBD (T415, G416, K417,D420, Y421, L455, F456, R457, K458, N460, Y473, A475, G476, 5477, F486,N487, Y489 and Q493) (FIG. 5T).

Antibody P5A-1D2 mainly uses the heavy chain for interactions with theRBD, and the paratope region consists of 20 residues from the heavychain (G26, F27, 128, S31, N32, Y33, Y52, S53, G54, S56, Y58, R87, R97,L99, Q100, V101, G102, A103, T104 and D106) and 3 residues from thelight chain (A31, Y33, S95) (FIG. 5T). The buried surface area on theRBD is shown in FIG. 5T and the recognized 20 epitope residues arelocated in the SARS-CoV-2 RBD (T415, G416, K417, D420, Y421, Y453, L455,F456, R457, K458, N460, Y473, Q474, A475, G476, S477, N487, Y489, Q493and Y505) (FIG. 5T).

Antibody P5A-3C8 mainly uses the heavy chain for interactions with theRBD, and the paratope region consists of 16 residues from the heavychain (G26, F27, T28, S31, N32, Y33, Y52, S53, G54, S56, Y58, R97, L99,Q100, E101 and H102) and 12 residues from the light chain (G28, 129,S30, S31, S67, G68, H90, L91, N92, S93 and Y94) (FIG. 5T). The buriedsurface area on the RBD is shown in FIG. 5T and the recognized 19epitope residues are located in the SARS-CoV-2 RBD (T415, G416, K417,D420, Y421, Y453, L455, F456, R457, K458, N460, Y473, A475, G476, S477,F486, N487, Y489 and Q493) (FIG. 5T).

Antibody P2C-1F11 mainly uses the heavy chain for interactions with theRBD, and the paratope region consists of 16 residues from the heavychain (G26, 127, T28, S31, N32, Y33, Y52, S53, G54, S56, R97, L99, V100,V101, Y102 and D105) and 3 residues from the light chain (S28, S30 andY33) (FIG. 5T). The buried surface area on the RBD is shown in FIG. 5Tand the recognized 19 epitope residues are located in the SARS-CoV-2 RBD(T415, G416, K417, D420, Y421, L455, F456, R457, K458, N460, Y473, Q474,A475, G476, S477, F486, N487, Y489 and Q493) (FIG. 5T).

In the shared HCDR1-RBD interface, the conserved HCDR1 residues G26,F27, T28/I28, S31, N32 and Y33 interact with RBD residues L455, K458,Y473, A475, G476, S477 and N487. In the shared HCDR2-RBD interface,interactions are largely mediated through HCDR2 residues Y52, S53, G54,S56 and Y58 and RBD residues T415, G416, K417, D420, Y421, K458 andN460. In particular, one unique feature shared by the four antibodies isthe participation of three conserved tyrosines (Y33, Y52 and Y58) informing a network of hydrophobic and hydrophilic interactions with theRBD (FIG. 5N). For example, the Y33 forms extensive hydrophobicinteractions with RBD K417, Y421, L455 and F456 (FIG. 5N). Its sidechain —OH also forms a conserved hydrogen bond with the main chainoxygen atom of RBD L455 (FIG. 5N). Another unique and shared feature isthe interactions mediated by the -SGGS- segment in the HCDR2. Apart fromthe close contacts through Van der Waals forces, specifichydrogen-bonding interactions also occur between the beginning S53 andending S56 with RBD Y421 and D420, respectively (FIG. 5O). In addition,RBD Y421 also forms a conserved hydrogen bond with main chain N atom ofthe G44 (FIG. 5O).

Despite of common and shared features, the four antibodies alsodemonstrated some minor differences due to their sequence and structurevariations. P22A-1D1, P5A-3C8, and P2C-1F11 have the same 11-residuelong HCDR3, but actual sequence varies. For example, the -RDYYG- inP22A-1D1 is replaced by -LQEHG- in P5A-3C8 and by -LVVYG- in P2C-1F11(Table 9b). Therefore, although interacting with the same RBD residuessuch as F456, N487, Y489 and Q493, the specific residues in the HCDR3 inmediating such interactions are different. Compared to the other three,P5A-1D2 has a relatively longer HCDR3 with 15 residues (FIG. 5K andTable 9b), providing more residues to interact with RBD. For instance,the T104 at the tip of the P5A-1D2 HCDR3 has interactions with RBD Y505,which is absent in other three HCDR3-RBD interfaces (FIG. 5K). RBD Y505is instead recognized by the light chain of P22A-1D1, P5A-3C8 andP2C-1F11, and appears to serves as an anchor residue for light chainbinding (FIG. 5P-FIG. 5S). However, recognition by the long HCDR3 ofP5A-1D2 resulted in significant change in the side chain conformation ofY505, precluding Y505 serving as an anchor for P5A-1D2 light chainbinding (FIG. 5P-FIG. 5S).

To further dissect the impact of epitope residues on the binding ofpublic antibodies, we conducted single-site alanine scanning mutagenesisfor the 15 epitope residues shared among the public antibodies. Allmutant spikes were successfully expressed on the surface of HEK 293Tcells, as measured by the median fluorescence intensity (MFI) of thecontrol S2 antibody through flow cytometry. However, of the 15 mutantresidues, 12 resulted in more than 80% reduction in the binding of thefour public antibodies although some antibodies are more sensitive thanothers (FIG. 6C, highlighted in grey boxes). For example, Y421A andF456A have broad impact on all four public antibodies, whereas T415A,Y473A, and N487A on three of the four. On the other hand, K417A, D420A,L455A, R457A, N460A, and Y489A only reduced binding for two of the fourantibodies. In particular, Y505A appears to have more profound impact onP5A-1D2 than the rest three antibodies. This is perhaps due to theimportance of Y505 in the heavy chain recognition through T104 at thetip of the HCDR3 as illustrated above. Taken together, these resultsindicate that some minor differences do exist among the four publicantibodies despite of their overall similarity, which may account fortheir minor differences in binding and neutralizing activities. Lastly,9 out of the 15 mutant residues also resulted in significant reductionof ACE2 binding to the surface expressed spike glycoprotein. Theseresidues are highlighted in orange boxes including T415A, Y421A, L455A,F456A, R457A, Y473A, N487A, Y489A, and Y505A. The shared impact of theseresidues on ACE2 and the public antibodies support the abovementionedstructural analysis (FIG. 5H-FIG. 5L).

EXAMPLE 7

Half-Life and Human PK Results in Healthy Adult Subjects.

The half-life of the monoclonal antibody (mAb) in a typical 70 kgsubject was determined:

mAb T_(1/2)=23.2 days (mAb with wild type human constant domain Fc)

mAb-YTE T_(1/2)=89.5 days (mAb with the YTE constant domain Fc)

The mAb1 and mAb2 antibodies were constructed and produced to containthe antigen-binding domain P2C-1F11 and P2B-1G5, respectively. Bothantibodies contain the modified human IgG constant domain comprising asubstitution with tyrosine at amino acid residue 252, a substitutionwith threonine at amino acid residue 254, and a substitution withglutamic acid at amino acid residue 256, numbered according to the EUindex as in Kabat.

Healthy human adult subjects were administered with the antibody atspecific dosages after obtaining consent according to protocols approvedby the institutional review board (IRB) (IRB approval number (025)-02and (026)-02, Ethical Committee of the Beijing Ditan Hospital, CapitalMedical University). Blood samples were taken at indicated time points.Quantitation of mAb1 and mAb2 serum concentrations was conducted using avalidated sandwich ELISA method using a commercially available His-tagSARS-CoV-2 Spike protein receptor binding domain as a capture reagent,and a commercially available mouse Anti-Human IgG Fc antibody labelledwith horseradish peroxidase as detection reagent.

Three dose levels were performed: cohort 1 (750 mg), cohort 2 (1500 mg)and cohort 3 (3000 mg).

Using the established human population PK model, mAb1 and mAb2 PKprofiles at different dose levels were measured and predicted usingMonte Carlo simulation. The predicted medians are shown in FIG. 15A-FIG.15B as solid lines for each cohort. Dashed lines and the dots representmeasured concentrations in the subjects. The shaded areas represent the5th-95th percentiles.

EXAMPLE 8

Neutralization Effect.

The neutralizing activity of the mAb1 and mAb2 alone or in combinationagainst live virus SARS-CoV-2 were measured using focus reductionneutralization test (FRNT) method. The two antibodies exhibited potentantiviral activity and the combination of two antibodies demonstrated amoderate additive effect in neutralizing live SARS-CoV-2 virus (FIG.16).

EXAMPLE 9

In Vivo Pharmacokinetics Assay.

The mAb1 and mAb2 single-dose PK was characterized after a 60-minutes IVinfusion administration of the mAb1 and mAb2, respectively, to male andfemale naïve cynomolgus monkeys at 10 mg/kg (n=3 animals per sex group).The animal study was conducted under the approved protocols.

Blood samples were collected at pre-dose, 5 min, 30 minutes, 1 hour, 2hours, 4 hours, 8 hours, 24 hours, 48 hours, 72 hours, 96 hours, 120hours, 168 hours, 240 hours, 336 hours, 504 hours, 672 hours, 840 hours,1008 hours, 1176 hours and 1344 hours post-end of infusion. Anti-drugantibody (ADA) samples were collected at pre-dose, 336 hours, 504 hours,672 hours, 840 hours, 1008 hours, 1176 hours, and 1344 hours post-end ofinfusion. Concentrations of mAb1 or mAb2 in serum samples weredetermined by an ELISA method. The level of ADA responses in collectedsamples were determined using a validated ECL method. Pharmacokineticnon-compartmental analyses (NCA) were based on the time of IV infusioninitiation time,

Pharmacokinetics (PK) data for the mAb1 and mAb2 in Cynomolgus Monkeyare shown in FIG. 17A (mAb1) and FIG. 17B (mAb2). mAb1 showed no markedsex differences at the dose level. Serum mAb1 and mAb2 concentrationsdeclined in a biphasic manner after a single 10 mg/kg IV dose, with aconcentration-time profile that indicated linear elimination.

All of the compositions and methods disclosed and claimed herein can bemade and executed without undue experimentation in light of the presentdisclosure. While the compositions and methods of this invention havebeen described in terms of preferred embodiments, it will be apparent tothose of skill in the art that variations may be applied to the methodsand in the steps or in the sequence of steps of the method describedherein without departing from the concept, spirit and scope of theinvention. More specifically, it will be apparent that certain agentswhich are both chemically and physiologically related may be substitutedfor the agents described herein while the same or similar results wouldbe achieved. All such similar substitutes and modifications apparent tothose skilled in the art are deemed to be within the spirit, scope andconcept of the invention as defined by the appended claims.

Numbered Embodiments of the Disclosure

Other subject matter contemplated by the present disclosure is set outin the following numbered embodiments:

-   1. An isolated or recombinant antibody or an antigen-binding    fragment thereof, which is capable of specifically binding to    SARS-CoV-2, and exhibiting at least 50% less binding or    non-detectable binding to SARS-CoV or MERS-CoV.-   2. An isolated or recombinant antibody or an antigen-binding    fragment thereof, having one or more features selected from the    group consisting of:

a) capable of specifically binding to spike protein of SARS-CoV-2 andexhibiting at least 50% less binding to spike protein of SARS-CoV orspike protein of MERS-CoV;

b) capable of specifically binding to receptor-binding domain (RBD) ofthe spike protein of SARS-CoV-2 comprising the amino acid sequence ofSEQ ID NO: 128;

c) exhibiting binding to RBD of spike protein of SARS-CoV comprising theamino acid sequence of SEQ ID NO: 124 at a level that is non-detectableor that is no more than 50% of the binding to the RBD of spike proteinof SARS-CoV-2;

d) exhibiting binding to RBD of spike protein of MERS-CoV comprising theamino acid sequence of SEQ ID NO: 126 at a level that is non-detectableor that is no more than 50% of the binding to RBD of the spike proteinof SARS-CoV-2;

e) capable of binding to the RBD of spike protein of SARS-CoV-2 at aK_(d) value of no more than 1×10⁻⁷M as measured by Surface PlasmonResonance (SPR);

f) exhibiting binding to the RBD of spike protein of SARS-CoV or the RBDof spike protein of MERS-CoV at a K_(d) value of at least 1×10⁻⁶M asmeasured by SPR;

g) capable of exhibiting at least 30% competition at with 2 μMangiotensin converting enzyme 2 (ACE2) receptor, for binding to the RBDof spike protein of SARS-CoV-2 immobilized at a resonance units (RU) of250, as measured by SPR; and

h) capable of binding to the RBD of spike protein of SARS-CoV-2 at aneutralizing activity at an IC₅₀ value of no more than 100 μg/ml, asmeasured by pseudovirus neutralization assay.

-   3. An isolated or recombinant antibody or an antigen-binding    fragment thereof capable of specifically binding to RBD of spike    protein of SARS-CoV-2, comprising:    -   a) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        1, SEQ ID NO: 2, and SEQ ID NO: 3;    -   b) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        11, SEQ ID NO: 12, and SEQ ID NO: 13;    -   c) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        21, SEQ ID NO: 22, and SEQ ID NO: 23;    -   d) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        31, SEQ ID NO: 32, and SEQ ID NO: 33;    -   e) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        41, SEQ ID NO: 42, and SEQ ID NO: 43;    -   f) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        51, SEQ ID NO: 52, and SEQ ID NO: 53;    -   g) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        65, SEQ ID NO: 66, and SEQ ID NO: 67;    -   h) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        75, SEQ ID NO: 76, and SEQ ID NO: 77;    -   i) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        85, SEQ ID NO: 86, and SEQ ID NO: 87;    -   j) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        95, SEQ ID NO: 96, and SEQ ID NO: 97;    -   k) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        105, SEQ ID NO: 106, and SEQ ID NO: 107;    -   l) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        136, SEQ ID NO: 137, and SEQ ID NO: 138;    -   m) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        146, SEQ ID NO: 147, and SEQ ID NO: 148;    -   n) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        156, SEQ ID NO: 157, and SEQ ID NO: 158;    -   o) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        166, SEQ ID NO: 167, and SEQ ID NO: 168;    -   p) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        176, SEQ ID NO: 177, and SEQ ID NO: 178;    -   q) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        186, SEQ ID NO: 187, and SEQ ID NO: 188;    -   r) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        196, SEQ ID NO: 197, and SEQ ID NO: 198;    -   s) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        206, SEQ ID NO: 207, and SEQ ID NO: 208;    -   t) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        216, SEQ ID NO: 217, and SEQ ID NO: 218;    -   u) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        226, SEQ ID NO: 227, and SEQ ID NO: 228;    -   v) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        236, SEQ ID NO: 237, and SEQ ID NO: 238;    -   w) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        246, SEQ ID NO: 247, and SEQ ID NO: 248;    -   x) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        256, SEQ ID NO: 257, and SEQ ID NO: 258;    -   y) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        266, SEQ ID NO: 267, and SEQ ID NO: 268;    -   z) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID NO:        276, SEQ ID NO: 277, and SEQ ID NO: 278;    -   aa) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 286, SEQ ID NO: 287, and SEQ ID NO: 288;    -   bb) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 296, SEQ ID NO: 297, and SEQ ID NO: 298;    -   cc) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 306, SEQ ID NO: 307, and SEQ ID NO: 308;    -   dd) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 316, SEQ ID NO: 317, and SEQ ID NO: 318;    -   ee) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 326, SEQ ID NO: 327, and SEQ ID NO: 328;    -   ff) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 336, SEQ ID NO: 337, and SEQ ID NO: 338;    -   gg) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 346, SEQ ID NO: 347, and SEQ ID NO: 348;    -   hh) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 356, SEQ ID NO: 357, and SEQ ID NO: 358;    -   ii) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 366, SEQ ID NO: 367, and SEQ ID NO: 368;    -   jj) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 376, SEQ ID NO: 377, and SEQ ID NO: 378;    -   kk) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 386, SEQ ID NO: 387, and SEQ ID NO: 388;    -   ll) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 396, SEQ ID NO: 397, and SEQ ID NO: 398;    -   mm) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 406, SEQ ID NO: 407, and SEQ ID NO: 408;    -   nn) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 416, SEQ ID NO: 417, and SEQ ID NO: 418; or    -   oo) 1, 2, or 3 heavy chain CDR sequences selected from SEQ ID        NO: 426, SEQ ID NO: 427, and SEQ ID NO: 428.-   4. The antibody or antigen binding fragment of any of the preceding    embodiments, comprising:    -   a) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        4, SEQ ID NO: 5, and SEQ ID NO: 6;    -   b) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        14, SEQ ID NO: 15, and SEQ ID NO: 16;    -   c) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        24, SEQ ID NO: 25 and SEQ ID NO: 26;    -   d) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        34, SEQ ID NO: 35 and SEQ ID NO: 36;    -   e) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        44, SEQ ID NO: 45 and SEQ ID NO: 46;    -   f) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        54, SEQ ID NO: 55 and SEQ ID NO: 56;    -   g) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        68, SEQ ID NO: 69, and SEQ ID NO: 70;    -   h) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        78, SEQ ID NO: 79, and SEQ ID NO: 80; and    -   i) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        88, SEQ ID NO: 89, and SEQ ID NO: 90.    -   j) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        98, SEQ ID NO: 99, and SEQ ID NO: 100;    -   k) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        108, SEQ ID NO: 109, and SEQ ID NO: 110;    -   l) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        139, SEQ ID NO: 140, and SEQ ID NO: 141;    -   m) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        149, SEQ ID NO: 150, and SEQ ID NO: 151;    -   n) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        159, SEQ ID NO: 160, and SEQ ID NO: 161;    -   o) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        169, SEQ ID NO: 170, and SEQ ID NO: 171;    -   p) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        179, SEQ ID NO: 180, and SEQ ID NO: 181;    -   q) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        189, SEQ ID NO: 190, and SEQ ID NO: 191;    -   r) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        199, SEQ ID NO: 200, and SEQ ID NO: 201;    -   s) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        209, SEQ ID NO: 210, and SEQ ID NO: 211;    -   t) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        219, SEQ ID NO: 220, and SEQ ID NO: 221;    -   u) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        229, SEQ ID NO: 230, and SEQ ID NO: 231;    -   v) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        239, SEQ ID NO: 240, and SEQ ID NO: 241;    -   w) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        249, SEQ ID NO: 250, and SEQ ID NO: 251;    -   x) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        259, SEQ ID NO: 260, and SEQ ID NO: 261;    -   y) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        269, SEQ ID NO: 270, and SEQ ID NO: 271;    -   z) 1, 2, or 3 light chain CDR sequences selected from SEQ ID NO:        279, SEQ ID NO: 280, and SEQ ID NO: 281;    -   aa) 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 289, SEQ ID NO: 290, and SEQ ID NO: 291;    -   bb) 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 299, SEQ ID NO: 300, and SEQ ID NO: 301;    -   cc) 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 309, SEQ ID NO: 310, and SEQ ID NO: 311;    -   dd) 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 319, SEQ ID NO: 320, and SEQ ID NO: 321;    -   ee) 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 329, SEQ ID NO: 330, and SEQ ID NO: 331;    -   ff) 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 339, SEQ ID NO: 340, and SEQ ID NO: 341;    -   gg) 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 349, SEQ ID NO: 350, and SEQ ID NO: 351;    -   hh) 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 359, SEQ ID NO: 360, and SEQ ID NO: 361;    -   ii) 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 369, SEQ ID NO: 370, and SEQ ID NO: 371;    -   jj) 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 379, SEQ ID NO: 380, and SEQ ID NO: 381;    -   kk) 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 389, SEQ ID NO: 390, and SEQ ID NO: 391;    -   ll) 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 399, SEQ ID NO: 400, and SEQ ID NO: 401;    -   mm) 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 409, SEQ ID NO: 410, and SEQ ID NO: 411;    -   nn) 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 419, SEQ ID NO: 420, and SEQ ID NO: 421; or    -   oo) 1, 2, or 3 light chain CDR sequences selected from SEQ ID        NO: 429, SEQ ID NO: 430, and SEQ ID NO: 431.-   5. The antibody or antigen binding fragment of any of the preceding    embodiments, comprising:    -   a) a heavy chain CDR1 (HCDR1) comprising the sequence of SEQ ID        NO: 1, a heavy chain CDR2 (HCDR2) comprising the sequence of SEQ        ID NO: 2, a heavy chain CDR3 (HCDR3) comprising the sequence of        SEQ ID NO: 3; a light chain CDR1 (LCDR1) comprising the sequence        of SEQ ID NO: 4, a light chain CDR2 (LCDR2) comprising the        sequence of SEQ ID NO: 5, and a light chain CDR3 (LCDR3)        comprising the sequence of SEQ ID NO: 6;    -   b) a HCDR1 comprising the sequence of SEQ ID NO: 11, a HCDR2        comprising the sequence of SEQ ID NO: 12, a HCDR3 comprising the        sequence of SEQ ID NO: 13, a LCDR1 comprising the sequence of        SEQ ID NO: 14, a LCDR2 comprising the sequence of SEQ ID NO: 15,        and a LCDR3 comprising the sequence of SEQ ID NO: 16;    -   c) a HCDR1 comprising the sequence of SEQ ID NO: 21, a HCDR2        comprising the sequence of SEQ ID NO: 22, a HCDR3 comprising the        sequence of SEQ ID NO: 23, a LCDR1 comprising the sequence of        SEQ ID NO: 24, a LCDR2 comprising the sequence of SEQ ID NO: 25,        and a LCDR3 comprising the sequence of SEQ ID NO: 26;    -   d) a HCDR1 comprising the sequence of SEQ ID NO: 31, a HCDR2        comprising the sequence of SEQ ID NO: 32, a HCDR3 comprising the        sequence of SEQ ID NO: 33, a LCDR1 comprising the sequence of        SEQ ID NO: 34, a LCDR2 comprising the sequence of SEQ ID NO: 35,        and a LCDR3 comprising the sequence of SEQ ID NO: 36;    -   e) a HCDR1 comprising the sequence of SEQ ID NO: 41, a HCDR2        comprising the sequence of SEQ ID NO: 42, a HCDR3 comprising the        sequence of SEQ ID NO: 43, a LCDR1 comprising the sequence of        SEQ ID NO: 44, a LCDR2 comprising the sequence of SEQ ID NO: 45,        and a LCDR3 comprising the sequence of SEQ ID NO: 46;    -   f) a HCDR1 comprising the sequence of SEQ ID NO: 51, a HCDR2        comprising the sequence of SEQ ID NO: 52, a HCDR3 comprising the        sequence of SEQ ID NO: 53, a LCDR1 comprising the sequence of        SEQ ID NO: 54, a LCDR2 comprising the sequence of SEQ ID NO: 55,        and a LCDR3 comprising the sequence of SEQ ID NO: 56;    -   g) a HCDR1 comprising the sequence of SEQ ID NO: 65, a HCDR2        comprising the sequence of SEQ ID NO: 66, a HCDR3 comprising the        sequence of SEQ ID NO: 67, a LCDR1 comprising the sequence of        SEQ ID NO: 68, a LCDR2 comprising the sequence of SEQ ID NO: 69,        and a LCDR3 comprising the sequence of SEQ ID NO: 70;    -   h) a HCDR1 comprising the sequence of SEQ ID NO: 75, a HCDR2        comprising the sequence of SEQ ID NO: 76, a HCDR3 comprising the        sequence of SEQ ID NO: 77, a LCDR1 comprising the sequence of        SEQ ID NO: 78, a LCDR2 comprising the sequence of SEQ ID NO: 79,        and a LCDR3 comprising the sequence of SEQ ID NO: 80;    -   i) a HCDR1 comprising the sequence of SEQ ID NO: 85, a HCDR2        comprising the sequence of SEQ ID NO: 86, a HCDR3 comprising the        sequence of SEQ ID NO: 87, a LCDR1 comprising the sequence of        SEQ ID NO: 88, a LCDR2 comprising the sequence of SEQ ID NO: 89,        and a LCDR3 comprising the sequence of SEQ ID NO: 90;    -   j) a HCDR1 comprising the sequence of SEQ ID NO: 95, a HCDR2        comprising the sequence of SEQ ID NO: 96, a HCDR3 comprising the        sequence of SEQ ID NO: 97, a LCDR1 comprising the sequence of        SEQ ID NO: 98, a LCDR2 comprising the sequence of SEQ ID NO: 99,        and a LCDR3 comprising the sequence of SEQ ID NO: 100;    -   k) a HCDR1 comprising the sequence of SEQ ID NO: 105, a HCDR2        comprising the sequence of SEQ ID NO: 106, a HCDR3 comprising        the sequence of SEQ ID NO: 107, a LCDR1 comprising the sequence        of SEQ ID NO: 108, a LCDR2 comprising the sequence of SEQ ID NO:        109, and a LCDR3 comprising the sequence of SEQ ID NO: 110;    -   l) a HCDR1 comprising the sequence of SEQ ID NO: 136, a HCDR2        comprising the sequence of SEQ ID NO: 137, a HCDR3 comprising        the sequence of SEQ ID NO: 138, a LCDR1 comprising the sequence        of SEQ ID NO: 139, a LCDR2 comprising the sequence of SEQ ID NO:        140, and a LCDR3 comprising the sequence of SEQ ID NO: 141;    -   m) HCDR1 comprising the sequence of SEQ ID NO: 146, a HCDR2        comprising the sequence of SEQ ID NO: 147, a HCDR3 comprising        the sequence of SEQ ID NO: 148, a LCDR1 comprising the sequence        of SEQ ID NO: 149, a LCDR2 comprising the sequence of SEQ ID NO:        150, and a LCDR3 comprising the sequence of SEQ ID NO: 151;    -   n) HCDR1 comprising the sequence of SEQ ID NO: 156, a HCDR2        comprising the sequence of SEQ ID NO: 157, a HCDR3 comprising        the sequence of SEQ ID NO: 158, a LCDR1 comprising the sequence        of SEQ ID NO: 159, a LCDR2 comprising the sequence of SEQ ID NO:        160, and a LCDR3 comprising the sequence of SEQ ID NO: 161;    -   o) HCDR1 comprising the sequence of SEQ ID NO: 166, a HCDR2        comprising the sequence of SEQ ID NO: 167, a HCDR3 comprising        the sequence of SEQ ID NO: 168, a LCDR1 comprising the sequence        of SEQ ID NO: 169, a LCDR2 comprising the sequence of SEQ ID NO:        170, and a LCDR3 comprising the sequence of SEQ ID NO: 171;    -   p) HCDR1 comprising the sequence of SEQ ID NO: 176, a HCDR2        comprising the sequence of SEQ ID NO: 177, a HCDR3 comprising        the sequence of SEQ ID NO: 178, a LCDR1 comprising the sequence        of SEQ ID NO: 179, a LCDR2 comprising the sequence of SEQ ID NO:        180, and a LCDR3 comprising the sequence of SEQ ID NO: 181;    -   q) HCDR1 comprising the sequence of SEQ ID NO: 186, a HCDR2        comprising the sequence of SEQ ID NO: 187, a HCDR3 comprising        the sequence of SEQ ID NO: 188, a LCDR1 comprising the sequence        of SEQ ID NO: 189, a LCDR2 comprising the sequence of SEQ ID NO:        190, and a LCDR3 comprising the sequence of SEQ ID NO: 191;    -   r) HCDR1 comprising the sequence of SEQ ID NO: 196, a HCDR2        comprising the sequence of SEQ ID NO: 197, a HCDR3 comprising        the sequence of SEQ ID NO: 198, a LCDR1 comprising the sequence        of SEQ ID NO: 199, a LCDR2 comprising the sequence of SEQ ID NO:        200, and a LCDR3 comprising the sequence of SEQ ID NO: 201;    -   s) HCDR1 comprising the sequence of SEQ ID NO: 206, a HCDR2        comprising the sequence of SEQ ID NO: 207, a HCDR3 comprising        the sequence of SEQ ID NO: 208, a LCDR1 comprising the sequence        of SEQ ID NO: 209, a LCDR2 comprising the sequence of SEQ ID NO:        210, and a LCDR3 comprising the sequence of SEQ ID NO: 211;    -   t) HCDR1 comprising the sequence of SEQ ID NO: 216, a HCDR2        comprising the sequence of SEQ ID NO: 217, a HCDR3 comprising        the sequence of SEQ ID NO: 218, a LCDR1 comprising the sequence        of SEQ ID NO: 219, a LCDR2 comprising the sequence of SEQ ID NO:        220, and a LCDR3 comprising the sequence of SEQ ID NO: 221;    -   u) HCDR1 comprising the sequence of SEQ ID NO: 226, a HCDR2        comprising the sequence of SEQ ID NO: 227, a HCDR3 comprising        the sequence of SEQ ID NO: 228, a LCDR1 comprising the sequence        of SEQ ID NO: 229, a LCDR2 comprising the sequence of SEQ ID NO:        230, and a LCDR3 comprising the sequence of SEQ ID NO: 231;    -   v) HCDR1 comprising the sequence of SEQ ID NO: 236, a HCDR2        comprising the sequence of SEQ ID NO: 237, a HCDR3 comprising        the sequence of SEQ ID NO: 238, a LCDR1 comprising the sequence        of SEQ ID NO: 239, a LCDR2 comprising the sequence of SEQ ID NO:        240, and a LCDR3 comprising the sequence of SEQ ID NO: 241;    -   w) HCDR1 comprising the sequence of SEQ ID NO: 246, a HCDR2        comprising the sequence of SEQ ID NO: 247, a HCDR3 comprising        the sequence of SEQ ID NO: 248, a LCDR1 comprising the sequence        of SEQ ID NO: 249, a LCDR2 comprising the sequence of SEQ ID NO:        250, and a LCDR3 comprising the sequence of SEQ ID NO: 251;    -   x) HCDR1 comprising the sequence of SEQ ID NO: 256, a HCDR2        comprising the sequence of SEQ ID NO: 257, a HCDR3 comprising        the sequence of SEQ ID NO: 258, a LCDR1 comprising the sequence        of SEQ ID NO: 259, a LCDR2 comprising the sequence of SEQ ID NO:        260, and a LCDR3 comprising the sequence of SEQ ID NO: 261;    -   y) HCDR1 comprising the sequence of SEQ ID NO: 266, a HCDR2        comprising the sequence of SEQ ID NO: 267, a HCDR3 comprising        the sequence of SEQ ID NO: 268, a LCDR1 comprising the sequence        of SEQ ID NO: 269, a LCDR2 comprising the sequence of SEQ ID NO:        270, and a LCDR3 comprising the sequence of SEQ ID NO: 271;    -   z) HCDR1 comprising the sequence of SEQ ID NO: 276, a HCDR2        comprising the sequence of SEQ ID NO: 277, a HCDR3 comprising        the sequence of SEQ ID NO: 278, a LCDR1 comprising the sequence        of SEQ ID NO: 279, a LCDR2 comprising the sequence of SEQ ID NO:        280, a LCDR3 comprising the sequence of SEQ ID NO: 281;    -   aa) HCDR1 comprising the sequence of SEQ ID NO: 286, a HCDR2        comprising the sequence of SEQ ID NO: 287, a HCDR3 comprising        the sequence of SEQ ID NO: 288, a LCDR1 comprising the sequence        of SEQ ID NO: 289, a LCDR2 comprising the sequence of SEQ ID NO:        290, a LCDR3 comprising the sequence of SEQ ID NO: 291;    -   bb) HCDR1 comprising the sequence of SEQ ID NO: 296, a HCDR2        comprising the sequence of SEQ ID NO: 297, a HCDR3 comprising        the sequence of SEQ ID NO: 298, a LCDR1 comprising the sequence        of SEQ ID NO: 299, a LCDR2 comprising the sequence of SEQ ID NO:        300, a LCDR3 comprising the sequence of SEQ ID NO: 301;    -   cc) HCDR1 comprising the sequence of SEQ ID NO: 306, a HCDR2        comprising the sequence of SEQ ID NO: 307, a HCDR3 comprising        the sequence of SEQ ID NO: 308, a LCDR1 comprising the sequence        of SEQ ID NO: 309, a LCDR2 comprising the sequence of SEQ ID NO:        310, a LCDR3 comprising the sequence of SEQ ID NO: 311;    -   dd) HCDR1 comprising the sequence of SEQ ID NO: 316, a HCDR2        comprising the sequence of SEQ ID NO: 317, a HCDR3 comprising        the sequence of SEQ ID NO: 318, a LCDR1 comprising the sequence        of SEQ ID NO: 319, a LCDR2 comprising the sequence of SEQ ID NO:        320, a LCDR3 comprising the sequence of SEQ ID NO: 321;    -   ee) HCDR1 comprising the sequence of SEQ ID NO: 326, a HCDR2        comprising the sequence of SEQ ID NO: 327, a HCDR3 comprising        the sequence of SEQ ID NO: 328, a LCDR1 comprising the sequence        of SEQ ID NO: 329, a LCDR2 comprising the sequence of SEQ ID NO:        330, a LCDR3 comprising the sequence of SEQ ID NO: 331;    -   ff) HCDR1 comprising the sequence of SEQ ID NO: 336, a HCDR2        comprising the sequence of SEQ ID NO: 337, a HCDR3 comprising        the sequence of SEQ ID NO: 338, a LCDR1 comprising the sequence        of SEQ ID NO: 339, a LCDR2 comprising the sequence of SEQ ID NO:        340, a LCDR3 comprising the sequence of SEQ ID NO: 341;    -   gg) HCDR1 comprising the sequence of SEQ ID NO: 346, a HCDR2        comprising the sequence of SEQ ID NO: 347, a HCDR3 comprising        the sequence of SEQ ID NO: 348, a LCDR1 comprising the sequence        of SEQ ID NO: 349, a LCDR2 comprising the sequence of SEQ ID NO:        350, a LCDR3 comprising the sequence of SEQ ID NO: 351;    -   hh) HCDR1 comprising the sequence of SEQ ID NO: 356, a HCDR2        comprising the sequence of SEQ ID NO: 357, a HCDR3 comprising        the sequence of SEQ ID NO: 358, a LCDR1 comprising the sequence        of SEQ ID NO: 359, a LCDR2 comprising the sequence of SEQ ID NO:        360, a LCDR3 comprising the sequence of SEQ ID NO: 361;    -   ii) HCDR1 comprising the sequence of SEQ ID NO: 366, a HCDR2        comprising the sequence of SEQ ID NO: 367, a HCDR3 comprising        the sequence of SEQ ID NO: 368, a LCDR1 comprising the sequence        of SEQ ID NO: 369, a LCDR2 comprising the sequence of SEQ ID NO:        370, a LCDR3 comprising the sequence of SEQ ID NO: 371;    -   jj) HCDR1 comprising the sequence of SEQ ID NO: 376, a HCDR2        comprising the sequence of SEQ ID NO: 377, a HCDR3 comprising        the sequence of SEQ ID NO: 378, a LCDR1 comprising the sequence        of SEQ ID NO: 379, a LCDR2 comprising the sequence of SEQ ID NO:        380, a LCDR3 comprising the sequence of SEQ ID NO: 381;    -   kk) HCDR1 comprising the sequence of SEQ ID NO: 386, a HCDR2        comprising the sequence of SEQ ID NO: 387, a HCDR3 comprising        the sequence of SEQ ID NO: 388, a LCDR1 comprising the sequence        of SEQ ID NO: 389, a LCDR2 comprising the sequence of SEQ ID NO:        390, a LCDR3 comprising the sequence of SEQ ID NO: 391;    -   ll) HCDR1 comprising the sequence of SEQ ID NO: 396, a HCDR2        comprising the sequence of SEQ ID NO: 397, a HCDR3 comprising        the sequence of SEQ ID NO: 398, a LCDR1 comprising the sequence        of SEQ ID NO: 399, a LCDR2 comprising the sequence of SEQ ID NO:        400, a LCDR3 comprising the sequence of SEQ ID NO: 401;    -   mm) HCDR1 comprising the sequence of SEQ ID NO: 406, a HCDR2        comprising the sequence of SEQ ID NO: 407, a HCDR3 comprising        the sequence of SEQ ID NO: 408, a LCDR1 comprising the sequence        of SEQ ID NO: 409, a LCDR2 comprising the sequence of SEQ ID NO:        410, a LCDR3 comprising the sequence of SEQ ID NO: 411;    -   nn) HCDR1 comprising the sequence of SEQ ID NO: 416, a HCDR2        comprising the sequence of SEQ ID NO: 417, a HCDR3 comprising        the sequence of SEQ ID NO: 418, a LCDR1 comprising the sequence        of SEQ ID NO: 419, a LCDR2 comprising the sequence of SEQ ID NO:        420, a LCDR3 comprising the sequence of SEQ ID NO: 421; or    -   oo) HCDR1 comprising the sequence of SEQ ID NO: 426, a HCDR2        comprising the sequence of SEQ ID NO: 427, a HCDR3 comprising        the sequence of SEQ ID NO: 428, a LCDR1 comprising the sequence        of SEQ ID NO: 429, a LCDR2 comprising the sequence of SEQ ID NO:        430, a LCDR3 comprising the sequence of SEQ ID NO: 431.-   6. The antibody or antigen binding fragment of any of the preceding    embodiments, comprising a pair of heavy chain variable region and    light chain variable region sequences selected from the group    consisting of: SEQ ID NOs: 7/8, 17/18, 27/28, 37/38, 47/48, 57/58,    61/62, 71/72, 81/82, 91/92, 101/102, 111/112, 142/143, 152/153,    162/163, 172/173, 182/183, 192/193, 202/203, 212/213, 222/223,    232/233, 242/243, 252/253, 262/263, 272/273, 282/283, 292/293,    302/303, 312/313, 322/323, 332/333, 342/343, 352/353, 362/363,    372/373, 382/383, 392/393, 402/403, 412/413, 422/423 and 432/433, or    a pair of homologous sequences thereof having at least 80% sequence    identity yet retaining binding specificity to RBD of spike protein    of SARS-CoV-2.-   7. The antibody or antigen binding fragment of embodiments 1 or 2,    which is a variant of antibody P2A-1A8, P2A-1A9, P2B-2G11, P2A-1A10,    P2A-1B3, P2B-2F6, P2B-2G4, P2C-1A3, P2C-1C8, P2C-1C10, P2C-1D5,    P2C-1F11, P2B-1G5, P2B-1A1, P2C-1D7, P2B-1A10, P2B-1D9, P2B-1E4,    P2B-1G1, P4A-2D9, P5A-2G7, P5A-3C8, P5A-1D2, P5A-2F11, P5A-2E1,    P5A-1C8, P1A-1C10, P4A-1H6, P4B-1F4, P5A-1B6, P5A-1B8, P5A-1B9,    P5A-1D1, P5A-1D10, P5A-2D11, P5A-2G9, P5A-2H3, P5A-3A1, P5A-3A6,    P5A-3B4, P5A-3C12, or P22A-1D1, which comprises:    -   a) a heavy chain CDR1 (HCDR1) sequence having at least 80% (e.g.        at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,        99%) sequence identity to a HCDR1 sequence of the parent        antibody listed in Table 1, and/or    -   b) a heavy chain CDR2 (HCDR2) sequence having at least 80% (e.g.        at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,        99%) sequence identity to a HCDR2 sequence of the parent        antibody listed in Table 1, and/or    -   c) a heavy chain CDR3 (HCDR3) sequence having at least 80% (e.g.        at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,        99%) sequence identity to a HCDR3 sequence of the parent        antibody listed in Table 1, and/or    -   d) a light chain CDR1 (LCDR1) sequence having at least 80% (e.g.        at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,        99%) sequence identity to a LCDR1 sequence of the parent        antibody listed in Table 1, and/or    -   e) a light chain CDR2 (LCDR2) sequence having at least 80% (e.g.        at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,        99%) sequence identity to a LCDR2 sequence of the parent        antibody listed in Table 1, and/or    -   f) a light chain CDR3 (LCDR3) sequence having at least 80% (e.g.        at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,        99%) sequence identity to a LCDR3 sequence of the parent        antibody listed in Table 1, and    -   which retains the binding specificity to SARS-COV-2, optionally        having binding affinity to SARS-COV-2 at a level similar to or        even higher than its parent antibody.-   8. The antibody or antigen binding fragment of embodiment 7, which    comprises an HCDR1 having no more than 3, 2, or 1 amino acid    mutations in a HCDR1 sequence of the parent antibody listed in Table    1, an HCDR2 having no more than 6, 5, 4, 3, 2, or 1 amino acid    mutations in a HCDR2 sequence of the parent antibody listed in Table    1, HCDR3 having no more than 6, 5, 4, 3, 2, or 1 amino acid    mutations in a HCDR3 sequence of the parent antibody listed in Table    1, LCDR1 having no more than 2 or 1 amino acid mutations in a LCDR1    sequence of the parent antibody listed in Table 1, LCDR2 having no    more than 3, 2, or 1 amino acid mutations in a LCDR2 sequence of the    parent antibody listed in Table 1, and/or LCDR3 having no more than    3, 2, or 1 amino acid mutations in a LCDR3 sequence of the parent    antibody listed in Table 1.-   9. The antibody or antigen binding fragment of any of the preceding    embodiments, which comprises:    -   a) at least one heavy chain CDR sequence having no more than 3,        2, or 1 amino acid substitutions in a heavy chain CDR sequence        of the parent antibody listed in Table 1, or    -   b) at least two heavy chain CDR sequences each having no more        than 3, 2, or 1 amino acid substitutions in a heavy chain CDR        sequence of the parent antibody listed in Table 1, or    -   c) three heavy chain CDR sequences each having no more than 3,        2, or 1 amino acid substitutions in a heavy chain CDR sequence        of the parent antibody listed in Table 1, or    -   d) at least one light chain sequence having no more than 3, 2,        or 1 amino acid substitutions in a heavy chain CDR sequence of        the parent antibody listed in Table 1, or    -   e) at least two light chain CDR sequences each having no more        than 3, 2, or 1 amino acid substitutions in a heavy chain CDR        sequence of the parent antibody listed in Table 1, or    -   f) three light chain CDR sequences each having no more than 3,        2, or 1 amino acid substitutions in a heavy chain CDR sequence        of the parent antibody listed in Table 1.-   10. The antibody or antigen binding fragment of embodiments 1 or 2,    which is a variant of antibody P2B-2F6 and comprises:    -   a) a heavy chain CDR1 (HCDR1) sequence having at least 80% (e.g.        at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,        99%) sequence identity to SEQ ID NO: 41, and/or    -   b) a heavy chain CDR2 (HCDR2) sequence having at least 80% (e.g.        at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,        99%) sequence identity to SEQ ID NO: 42, and/or    -   c) a heavy chain CDR3 (HCDR3) sequence having at least 80% (e.g.        at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,        99%) sequence identity to SEQ ID NO: 43, and/or    -   d) a light chain CDR1 (LCDR1) sequence having at least 80% (e.g.        at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,        99%) sequence identity to SEQ ID NO: 44, and/or    -   e) a light chain CDR2 (LCDR2) sequence having at least 80% (e.g.        at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,        99%) sequence identity to SEQ ID NO: 45, and/or    -   f) a light chain CDR3 (LCDR3) sequence having at least 80% (e.g.        at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,        99%) sequence identity to SEQ ID NO: 46, and    -   which retains the binding specificity to SARS-COV-2, optionally        having binding affinity to SARS-COV-2 at a level similar to or        even higher than antibody P2B-2F6.-   11. The antibody or antigen binding fragment of embodiment 10, which    comprises an HCDR1 having no more than 4, 3, 2, or 1 amino acid    mutations in SEQ ID NO: 41, an HCDR2 having no more than 3, 2, or 1    amino acid mutations in SEQ ID NO: 42, HCDR3 having no more than 6,    5, 4, 3, 2, or 1 amino acid substitutions in SEQ ID NO: 43, LCDR1    having no more than 4, 3, 2, or 1 amino acid mutations in SEQ ID NO:    44, LCDR2 having no more than 3, 2, or 1 amino acid mutations in SEQ    ID NO: 45, and/or LCDR3 having no more than 4, 3, 2, or 1 amino acid    mutations in SEQ ID NO: 46.-   12. The antibody or antigen binding fragment of embodiments 10 or    11, which retains the entirety of or at least part of the paratope    of antibody P2B-2F6 while one or more of the amino acid residues    outside the paratope of the antibody may be mutated.-   13. The antibody or antigen binding fragment of embodiment 12,    wherein the paratope of antibody P2B-2F6 comprises or consists of:    Y27, S28, S30, S31, and Y33 of HCDR1, H54 of HCDR2, G102, I103,    V105, V106 and P107 of HCDR3, and G31, Y32 and N33 of LCDR1, wherein    the numbering of residues in the heavy chain CDRs is according to    SEQ ID NO: 47, and the numbering of residues in the light chain CDR    is according to SEQ ID NO: 48.-   14. The antibody or antigen binding fragment of embodiments 1 or 2,    which is a variant of antibody P2C-1F11, which comprises:    -   a) a heavy chain CDR1 (HCDR1) sequence having at least 80% (e.g.        at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,        99%) sequence identity to SEQ ID NO: 105, and/or    -   b) a heavy chain CDR2 (HCDR2) sequence having at least 80% (e.g.        at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,        99%) sequence identity to SEQ ID NO: 106, and/or    -   c) a heavy chain CDR3 (HCDR3) sequence having at least 80% (e.g.        at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,        99%) sequence identity to SEQ ID NO: 107, and/or    -   d) a light chain CDR1 (LCDR1) sequence having at least 80% (e.g.        at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,        99%) sequence identity to SEQ ID NO: 108, and/or    -   e) a light chain CDR2 (LCDR2) sequence having at least 80% (e.g.        at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,        99%) sequence identity to SEQ ID NO: 109, and/or    -   f) a light chain CDR3 (LCDR3) sequence having at least 80% (e.g.        at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,        99%) sequence identity to SEQ ID NO: 110, and    -   which retains the binding specificity to SARS-COV-2, optionally        having binding affinity to SARS-COV-2 at a level similar to or        even higher than antibody P2C-1F11.-   15. The antibody or antigen binding fragment of embodiment 14, which    comprises an HCDR1 having no more than 4, 3, 2, or 1 amino acid    mutations in SEQ ID NO: 105, an HCDR2 having no more than 3, 2, or 1    amino acid mutations in SEQ ID NO: 106, HCDR3 having no more than 6,    5, 4, 3, 2, or 1 amino acid mutations in SEQ ID NO: 107, LCDR1    having no more than 4, 3, 2, or 1 amino acid mutations in SEQ ID NO:    108, LCDR2 having no more than 3, 2, or 1 amino acid mutations in    SEQ ID NO: 109, and/or LCDR3 having no more than 4, 3, 2, or 1 amino    acid mutations in SEQ ID NO: 110, and in the meantime retain the    binding specificity to SARS-COV-2, optionally having binding    affinity to SARS-COV-2 at a level similar to or even higher than    antibody P2C-1F11.-   16. The antibody or antigen binding fragment of embodiment 14, which    retains the entirety of or at least part of the paratope of antibody    P2C-1F11 while one or more of the amino acid residues outside the    paratope of the antibody may be mutated.-   17. The antibody or antigen binding fragment of embodiment 16,    wherein the paratope of antibody P2C-1F11 comprises or consists of:    G26, 127, T28, S31, N32 and Y33 of HCDR1, Y52, S53, G54, and S56 of    HCDR2, R97, L99, V100, V101, Y102 and D105 of HCDR3, and S28, S30    and Y33 of LCDR1 of LCDR1, wherein the numbering of residues in    heavy chain is according to SEQ ID NO: 111, and the numbering of    residues in light chain CDR is according to SEQ ID NO: 112.-   18. The antibody or antigen binding fragment of embodiments 1 or 2,    which is a variant of antibody P22A-1D1, wherein the variant    comprises:

a) a heavy chain CDR1 (HCDR1) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 426, and/or

b) a heavy chain CDR2 (HCDR2) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 427, and/or

c) a heavy chain CDR3 (HCDR3) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 428, and/or

d) a light chain CDR1 (LCDR1) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 429, and/or

e) a light chain CDR2 (LCDR2) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 430, and/or

f) a light chain CDR3 (LCDR3) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 431, and

in the meantime retain the binding specificity to SARS-COV-2, optionallyhaving binding affinity to SARS-COV-2 at a level similar to or evenhigher than antibody P22A-1D1.

-   19. The antibody or antigen binding fragment of embodiment 18, which    comprises an HCDR1 having no more than 6, 5, 4, 3, 2, or 1 amino    acid mutations in SEQ ID NO: 426, an HCDR2 having no more than 5, 4,    3, 2, or 1 amino acid mutations in SEQ ID NO: 427, an HCDR3 having    no more than 6, 5, 4, 3, 2, or 1 amino acid substitutions in SEQ ID    NO: 428, an LCDR1 having no more than 5, 4, 3, 2, or 1 amino acid    mutations in SEQ ID NO: 429, LCDR2 having no more than 1 amino acid    mutations in SEQ ID NO: 430, and/or LCDR3 having no more than 4, 3,    2, or 1 amino acid mutations in SEQ ID NO: 431, and in the meantime    retain the binding specificity to SARS-COV-2, optionally having    binding affinity to SARS-COV-2 at a level similar to or even higher    than antibody P22A-1D1.-   20. The antibody or antigen binding fragment of embodiment 18, which    retain the entirety of the paratope of antibody P22A-1D1 while one    or more of the amino acid residues outside the paratope of the    antibody may be mutated.-   21. The antibody or antigen binding fragment of embodiments 20,    wherein the paratope of antibody P22A-1D1 comprises or consists of:    G26, F27, T28, S31, N32 and Y33 of HCDR1; Y52, S53, G54, and S56 of    HCDR2, Y58 of heavy chain framework region 3; R97, R99, D100, Y101,    Y102 and D105 of HCDR3; Q27, G28, 129, S30 and Y32 of LCDR1; S67 of    LCDR2; and/or H90, L91, N92 and Y94 of LCDR3; wherein the numbering    of residues in the heavy chain CDRs is according to SEQ ID NO: 432,    and the numbering of residues in the light chain CDR is according to    SEQ ID NO: 433.-   22. The antibody or antigen binding fragment of embodiments 1 or 2,    which is a variants of antibody P5A-1D2, wherein the variant    comprises:

a) a heavy chain CDR1 (HCDR1) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 236, and/or

b) a heavy chain CDR2 (HCDR2) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 237, and/or

c) a heavy chain CDR3 (HCDR3) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 238, and/or

d) a light chain CDR1 (LCDR1) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 239, and/or

e) a light chain CDR2 (LCDR2) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 240, and/or

f) a light chain CDR3 (LCDR3) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 241, and

in the meantime retain the binding specificity to SARS-COV-2, optionallyhaving binding affinity to SARS-COV-2 at a level similar to or evenhigher than antibody P5A-1D2.

-   23. The antibody or antigen binding fragment of embodiment 22, which    comprises an HCDR1 having no more than 4, 3, 2, or 1 amino acid    mutations in SEQ ID NO: 236, an HCDR2 having no more than 3, 2, or 1    amino acid mutations in SEQ ID NO: 237, HCDR3 having no more than 6,    5, 4, 3, 2, or 1 amino acid substitutions in SEQ ID NO: 238, LCDR1    having no more than 4, 3, 2, or 1 amino acid mutations in SEQ ID NO:    239, LCDR2 having no more than 3, 2, or 1 amino acid mutations in    SEQ ID NO: 240, and/or LCDR3 having no more than 4, 3, 2, or 1 amino    acid mutations in SEQ ID NO: 241, and in the meantime retain the    binding specificity to SARS-COV-2, optionally having binding    affinity to SARS-COV-2 at a level similar to or even higher than    antibody P5A-1D2.-   24. The antibody or antigen binding fragment of embodiment 22, which    retain the entirety of the paratope of antibody P5A-1D2 while one or    more of the amino acid residues outside the paratope of the antibody    may be mutated.-   25. The antibody or antigen binding fragment of embodiment 24,    wherein the paratope of antibody P5A-1D2 comprises or consists of:    G26, F27, 128, S31, N32 and Y33 of HCDR1; Y52, S53, G54, and S56 of    HCDR2; Y58 and R87 of heavy chain framework region 3, R97, L99,    Q100, V101, G102, A103, T104 and D106 of HCDR3; A31 and Y33 of    LCDR1; and/or S95 of LCDR3; wherein the numbering of residues in the    heavy chain CDRs is according to SEQ ID NO: 242, and the numbering    of residues in the light chain CDR is according to SEQ ID NO: 243.-   26. The antibody or antigen binding fragment of embodiments 1 or 2,    which is a variants of antibody P5A-3C8, wherein the variant    comprises:

a) a heavy chain CDR1 (HCDR1) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 226, and/or

b) a heavy chain CDR2 (HCDR2) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 227, and/or

c) a heavy chain CDR3 (HCDR3) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 228, and/or

d) a light chain CDR1 (LCDR1) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 229, and/or

e) a light chain CDR2 (LCDR2) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 230, and/or

f) a light chain CDR3 (LCDR3) sequence having at least 80% (e.g. atleast 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%)sequence identity to SEQ ID NO: 231, and

in the meantime retain the binding specificity to SARS-COV-2, optionallyhaving binding affinity to SARS-COV-2 at a level similar to or evenhigher than antibody P5A-3C8.

-   27. The antibody or antigen binding fragment of embodiment 26, which    comprises an HCDR1 having no more than 4, 3, 2, or 1 amino acid    mutations in SEQ ID NO: 226, an HCDR2 having no more than 3, 2, or 1    amino acid mutations in SEQ ID NO: 227, HCDR3 having no more than 6,    5, 4, 3, 2, or 1 amino acid substitutions in SEQ ID NO: 228, LCDR1    having no more than 4, 3, 2, or 1 amino acid mutations in SEQ ID NO:    229, LCDR2 having no more than 3, 2, or 1 amino acid mutations in    SEQ ID NO: 230, and/or LCDR3 having no more than 4, 3, 2, or 1 amino    acid mutations in SEQ ID NO: 231, and in the meantime retain the    binding specificity to SARS-COV-2, optionally having binding    affinity to SARS-COV-2 at a level similar to or even higher than    antibody P5A-3C8.-   28. The antibody or antigen binding fragment of embodiment 26, which    retain the entirety of the paratope of antibody P5A-3C8 while one or    more of the amino acid residues outside the paratope of the antibody    may be mutated.-   29. The antibody or antigen binding fragment of embodiment 28,    wherein the paratope of antibody P5A-3C8 comprises or consists of:    G26, F27, T28, S31, N32 and Y33 of HCDR1; Y52, S53, G54, and S56 of    HCDR2; Y58 of heavy chain framework region 3, R97, L99, Q100, E101    and H102 of HCDR3; and G28, 129, S30, S31 and Y32 of LCDR1; S67 of    LCDR2; G68 of light chain framework region 3, H90, L91, N92, S93 and    Y94 of LCDR3; wherein the numbering of residues in the heavy chain    CDRs is according to SEQ ID NO: 232, and the numbering of residues    in the light chain CDR is according to SEQ ID NO: 233.-   30. The antibody or antigen binding fragment of any of the preceding    embodiments, further comprising an immunoglobulin constant region,    optionally a constant region of human immunoglobulin, or optionally    a constant region of human IgG.-   31. The antibody or antigen binding fragment of any of the preceding    embodiments, further comprising one or more amino acid residue    mutations yet retains binding specificity to SARS-CoV-2, optionally    binding affinity to RBD of spike protein of SARS-CoV-2.-   32. The antibody or antigen binding fragment of embodiment 31, which    is an affinity variant, a glycosylation variant, a    cysteine-engineered variant, or an Fc variant.-   33. The antibody or antigen binding fragment of embodiment 32,    wherein the Fc variant comprises one or more amino acid residue    modifications or substitutions resulting in increased effector    functions relative to a wildtype Fc.-   34. The antibody or antigen binding fragment of embodiment 33,    wherein the Fc variant comprises one or more amino acid    substitution(s) at one or more of the following positions: 234, 235,    236, 238, 239, 240, 241, 243, 244, 245, 246, 247, 248, 249, 252,    254, 255, 256, 258, 260, 262, 263, 264, 265, 267, 268, 269, 270,    272, 274, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294,    295, 296, 298, 299, 300, 301, 303, 304, 305, 307, 309, 312, 313,    315, 320, 322, 324, 325, 326, 327, 329, 330, 331, 332, 333, 334,    335, 337, 338, 339, 340, 345, 360, 373, 376, 378, 382, 388, 389,    396, 398, 414, 416, 419, 430, 433, 434, 435, 436, 437, 438, 439 and    440 of the Fc region, wherein the numbering of the residues in the    Fc region is that of the EU index as in Kabat.-   35. The antibody or antigen binding fragment of embodiment 34,    wherein the Fc variant comprises one or more amino acid substitution    selected from the group consisting of 234Y, 235Q, 236A, 236W, 239D,    239E, 239M, 243L, 2471, 267E, 268D, 268E, 268F, 270E, 280H, 290S,    292P, 298A, 298D, 298V, 300L, 3051, 324T, 326A, 326D, 326W, 330L,    330M, 333S, 332D, 332E, 298A, 333A, 334A, 334E, 339D, 339Q, 345R,    396L, 430G, 440Y, or any combination thereof.-   36. The antibody or antigen binding fragment of embodiment 33,    wherein the Fc variant comprises one or more amino acid residue    modifications or substitutions resulting in reduced effector    functions relative to a wildtype Fc.-   37. The antibody or antigen binding fragment of embodiment 36,    wherein the Fc variant comprises one or more amino acid    substitution(s) at a position selected from the group consisting of:    220, 226, 229, 233, 234, 235, 236, 237, 238, 267, 268, 269, 270,    297, 309, 318, 320, 322, 325, 328, 329, 330, and 331 of the Fc    region, wherein the numbering of the residues in the Fc region is    that of the EU index as in Kabat.-   38. The antibody or antigen binding fragment of embodiment 36,    wherein the Fc variant comprises one or more amino acid    substitution(s) selected from the group consisting of 220S, 226S,    228P, 229S, 233P, 234V, 234G, 234A, 234F, 234A, 235A, 235G, 235E,    236E, 236R, 237A, 237K, 238S, 267R, 268A, 268Q, 269R, 297A, 297Q,    297G, 309L, 318A, 322A, 325L, 328R, 330S, 331S, and any combination    thereof.-   39. The antibody or antigen binding fragment of embodiment 33,    wherein the Fc variant comprises one or more amino acid residue    modifications or substitutions resulting in improved serum half-life    or improved binding affinity to neonatal Fc receptor (FcRn) at pH    6.0 while retaining minimal binding at pH 7.4.-   40. The antibody or antigen binding fragment of embodiment 39,    wherein the Fc variant comprises one or more amino acid    substitution(s) at a position selected from the group consisting of:    234, 235, 238, 250, 252, 254, 256; 259; 272, 305, 307, 308, 311,    312, 322, 328, 331, 378, 380, 382, 428, 432, 433, 434, 435, 436 and    437 (all positions by EU numbering).-   41. The antibody or antigen binding fragment of embodiment 40,    wherein the Fc variant comprises one or more amino acid    substitution(s) selected from the group consisting of 234F, 235Q,    238D, 250Q, 252T, 252Y, 254T, 256E, 2591, 272A, 305A, 307A, 308F,    311A, 322Q, 328E, 331S, 380A, 428L, 432C, 433K, 433S, 434S, 434Y,    434F, 434W, 434A, 435H, 436L, 437C and any combination thereof.-   42. The antibody or antigen binding fragment of embodiment 31,    wherein at least one of the substitutions or modifications is in one    or more of the CDR sequences, and/or in one or more of the non-CDR    sequences of the heavy chain variable region or light chain variable    region.-   43. The antibody or an antigen-binding fragment thereof of any one    of the preceding embodiments, which is a monoclonal antibody, a    bispecific antibody, a multi-specific antibody, a recombinant    antibody, a chimeric antibody, a labeled antibody, a bivalent    antibody, an anti-idiotypic antibody, a fusion protein, a dimerized    or polymerized antibody, or a modified antibody (e.g. glycosylated    antibody).-   44. The antibody or antigen binding fragment of any of the preceding    embodiments, which is a diabody, a Fab, a Fab′, a F(ab′)₂, a Fd, an    Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv)₂, a    bispecific dsFv (dsFv-dsFv′), a disulfide stabilized diabody (ds    diabody), a single-chain antibody molecule (scFv), an scFv dimer    (bivalent diabody), a bispecific scFv dimer, a multispecific    antibody, a heavy chain antibody, a camelized single domain    antibody, a nanobody, a domain antibody, or a bivalent domain    antibody.-   45. The antibody or antigen binding fragment of any of preceding    embodiments, which is bispecific and comprises a first    antigen-binding domain and a second antigen-binding domain, wherein    the first and the second antigen-binding domains are derived from    any two monoclonal antibodies selected from the group consisting of    P2A-1A8, P2A-1A9, P2B-2G11, P2A-1A10, P2A-1B3, P2B-2F6, P2B-2G4,    P2C-1A3, P2C-1C8, P2C-1C10, P2C-1D5, P2C-1F11, P2B-1G5, P2B-1A1,    P2C-1D7, P2B-1A10, P2B-1D9, P2B-1E4, P2B-1G1, P4A- 2D9, P5A-2G7,    P5A-3C8, P5A-1D2, P5A-2F11, P5A-2E1, P2A-1A8, P2A-1A9, P2B-2G11,    P2A-1A10, P2A-1B3, P2B-2F6, P2B-2G4, P2C-1A3, P2C-1C8, P2C-1C10,    P2C-1D5, P2C- 1F11, P2B-1G5, P2B-1A1, P2C-1D7, P2B-1A10, P2B-1D9,    P2B-1E4, P2B-1G1, P4A-2D9, P5A-2G7, P5A-3C8, P5A-1D2, P5A-2F11,    P5A-2E1, P5A-1C8, P1A-1C10, P4A-1H6, P4B- 1F4, P5A-1B6, P5A-1B8,    P5A-1B9, P5A-1D1, P5A-1D10, P5A-2D11, P5A-2G9, P5A-2H3, P5A-3A1,    P5A-3A6, P5A-3B4, P5A-3C12, and P22A-1D1.-   46. The antibody or antigen binding fragment of embodiment 45,    wherein the first and the second antigen-binding domains are    derived:

a) from P2C-1F11 and P2B-2F6, respectively;

b) from P2C-1F11 and P2A-1A8, respectively;

c) from P2C-1F11 and P2A-1A9, respectively;

d) from P2C-1F11 and P2B-2G11, respectively;

e) from P2C-1F11 and P2A-1A10, respectively;

f) from P2C-1F11 and P2A-1B3, respectively;

g) from P2C-1F11 and P2B-2G4, respectively;

h) from P2C-1F11 and P2C-1A3, respectively;

i) from P2C-1F11 and P2C-1C8, respectively;

j) from P2C-1F11 and P2C-1C10, respectively;

k) from P2C-1F11 and P2C-1D5, respectively;

l) from P2A-1A8 and P2A-1A9, respectively;

m) from P2A-1A8 and P2B-2G11, respectively;

n) from P2A-1A8 and P2A-1A10, respectively;

o) from P2A-1A8 and P2A-1B3, respectively;

p) from P2A-1A8 and P2B-2F6, respectively;

q) from P2A-1A8 and P2B-2G4, respectively;

r) from P2A-1A8 and P2C-1A3, respectively;

s) from P2A-1A8 and P2C-1C8, respectively;

t) from P2A-1A8 and P2C-1C10, respectively;

u) from P2A-1A8 and P2C-1D5, respectively;

v) from P2A-1A9 and 2B-2G11, respectively;

w) from P2A-1A9 and P2A-1A10, respectively;

x) from P2A-1A9 and P2A-1B3, respectively;

y) from P2A-1A9 and P2B-2F6, respectively;

z) from P2A-1A9 and P2B-2G4, respectively;

aa) from P2A-1A9 and P2C-1A3, respectively;

bb) from P2A-1A9 and P2C-1C8, respectively;

cc) from P2A-1A9 and P2C-1C10, respectively;

dd) from P2A-1A9 and P2C-1D5, respectively;

ee) from P2B-2G11 and P2A-1A10, respectively;

ff) from P2B-2G11 and P2A-1B3, respectively;

gg) from P2B-2G11 and P2B-2F6, respectively;

hh) from P2B-2G11 and P2B-2G4, respectively;

ii) from P2B-2G11 and P2C-1A3, respectively;

jj) from P2B-2G11 and P2C-1C8, respectively;

kk) from P2B-2G11 and P2C-1C10, respectively;

ll) from P2B-2G11 and P2C-1D5, respectively;

mm) from P2A-1A10 and P2A-1B3, respectively;

nn) from P2A-1A10 and P2B-2F6, respectively;

oo) from P2A-1A10 and P2B-2G4, respectively;

pp) from P2A-1A10 and P2C-1A3, respectively;

qq) from P2A-1A10 and P2C-1C8, respectively;

rr) from P2A-1A10 and P2C-1C10, respectively;

ss) from P2A-1A10 and P2C-1D5, respectively;

tt) from P2A-1B3 and P2B-2F6, respectively;

uu) from P2A-1B3 and P2B-2G4, respectively;

vv) from P2A-1B3 and P2C-1A3, respectively;

ww) from P2A-1B3 and P2C-1C8, respectively;

xx) from P2A-1B3 and P2C-1C10, respectively;

yy) from P2A-1B3 and P2C-1D5, respectively;

zz) from P2B-2F6 and P2B-2G4, respectively;

aaa) from P2B-2F6 and P2C-1A3, respectively;

bbb) from P2B-2F6 and P2C-1C8, respectively;

ccc) from P2B-2F6 and P2C-1C10, respectively;

ddd) from P2B-2F6 and P2C-1D5, respectively;

eee) from P2B-2G4 and P2C-1A3, respectively;

fff) from P2B-2G4 and P2C-1C8, respectively;

ggg) from P2B-2G4 and P2C-1C10, respectively;

hhh) from P2B-2G4 and P2C-1D5, respectively;

iii) from P2C-1A3 and P2C-1C8, respectively;

jjj) from P2C-1A3 and P2C-1C10, respectively;

kkk) from P2C-1A3 and P2C-1D5, respectively;

lll) from P2C-1C8 and P2C-1C10, respectively;

mmm) from P2C-1C8 and P2C-1D5, respectively; or

nnn) from P2C-1C10 and P2C-1D5, respectively.

-   47. The antibody or antigen binding fragment of embodiments 1 or 2,    which is bispecific and comprises a first antigen-binding domain and    a second antigen-binding domain, wherein the first and the second    antigen-binding domains are derived from any two monoclonal    antibodies selected from the group consisting of P2C-1F11, P2B-2F6,    P2B-1G5, P2B-1A1, P2C-1D7, P2B-1A10, P2B-1D9, P2B-1E4, P2B-1G1,    P4A-2D9, P5A-2G7, P5A-3C8, P5A-1D2, P5A-2F11, P5A-2E1, P2A-1A8,    P2A-1A9, P2B-2G11, P2A-1A10, P2A-1B3, P2B-2F6, P2B-2G4, P2C-1A3,    P2C-1C8, P2C-1C10, P2C-1D5, P2C-1F11, P2B-1G5, P2B-1A1, P2C- 1D7,    P2B-1A10, P2B-1D9, P2B-1E4, P2B-1G1, P4A-2D9, P5A-2G7, P5A-3C8,    P5A-1D2, P5A-2F11, P5A-2E1, P5A-1C8, P1A-1C10, P4A-1H6, P4B-1F4,    P5A-1B6, P5A-1B8, P5A- 1B9, P5A-1D1, P5A-1D10, P5A-2D11, P5A-2G9,    P5A-2H3, P5A-3A1, P5A-3A6, P5A-3B4, P5A-3C12, and P22A-1D1.-   48. The antibody or antigen binding fragment of embodiment 47,    wherein the first and the second antigen-binding domains are    derived:

a) from P2C-1F11 and P2B-1G5, respectively;

b) from P2C-1F11 and P2B-1A1, respectively;

c) from P2C-1F11 and P2C-1D7, respectively;

d) from P2C-1F11 and P2B-1A10, respectively;

e) from P2C-1F11 and P2B-1D9, respectively;

f) from P2C-1F11 and P2B-1E4, respectively;

g) from P2C-1F11 and P2B-1G1, respectively;

h) from P2C-1F11 and P4A-2D9, respectively;

i) from P2C-1F11 and P5A-2G7, respectively;

j) from P2C-1F11 and P5A-3C8, respectively;

k) from P2C-1F11 and P5A-1D2, respectively;

l) from P2C-1F11 and P5A-2F11, respectively;

m) from P2C-1F11 and P5A-2E1, respectively;

n) from P2C-1F11 and P5A-1C8, respectively;

o) from P2B-2F6 and P2B-1G5, respectively;

p) from P2B-2F6 and P2B-1A1, respectively;

q) from P2B-2F6 and P2C-1D7, respectively;

r) from P2B-2F6 and P2B-1A10, respectively;

s) from P2B-2F6 and P2B-1D9, respectively;

t) from P2B-2F6 and P2B-1E4, respectively;

u) from P2B-2F6 and P2B-1G1, respectively;

v) from P2B-2F6 and P4A-2D9, respectively;

w) from P2B-2F6 and P5A-2G7, respectively;

x) from P2B-2F6 and P5A-3C8, respectively;

y) from P2B-2F6 and P5A-1D2, respectively;

z) from P2B-2F6 and P5A-2F11, respectively;

aa) from P2B-2F6 and P5A-2E1, respectively;

bb) from P2B-2F6 and P5A-1C8, respectively;

cc) from P2B-1G5 and P2B-1A1, respectively;

dd) from P2B-1G5 and P2C-1D7, respectively;

ee) from P2B-1G5 and P2B-1A10, respectively;

ff) from P2B-1G5 and P2B-1D9, respectively;

gg) from P2B-1G5 and P2B-1E4, respectively;

hh) from P2B-1G5 and P2B-1G1, respectively;

ii) from P2B-1G5 and P4A-2D9, respectively;

jj) from P2B-1G5 and P5A-2G7, respectively;

kk) from P2B-1G5 and P5A-3C8, respectively;

ll) from P2B-1G5 and P5A-1D2, respectively;

mm) from P2B-1G5 and P5A-2F11, respectively;

nn) from P2B-1G5 and P5A-2E1, respectively;

oo) from P2B-1G5 and P5A-1C8, respectively;

pp) from P2B-1A1 and P2C-1D7, respectively;

qq) from P2B-1A1 and P2B-1A10, respectively;

rr) from P2B-1A1 and P2B-1D9, respectively;

ss) from P2B-1A1 and P2B-1E4, respectively;

tt) from P2B-1A1 and P2B-1G1, respectively;

uu) from P2B-1A1 and P4A-2D9, respectively;

vv) from P2B-1A1 and P5A-2G7, respectively;

ww) from P2B-1A1 and P5A-3C8, respectively;

xx) from P2B-1A1 and P5A-1D2, respectively;

yy) from P2B-1A1 and P5A-2F11, respectively;

zz) from P2B-1A15 and P5A-2E1, respectively;

aaa) from P2B-1A1 and P5A-1C8, respectively;

bbb) from P2C-1D7 and P2B-1A10, respectively;

ccc) from P2C-1D7 and P2B-1D9, respectively;

ddd) from P2C-1D7 and P2B-1E4, respectively;

eee) from P2C-1D7 and P2B-1G1, respectively;

fff) from P2C-1D7 and P4A-2D9, respectively;

ggg) from P2C-1D7 and P5A-2G7, respectively;

hhh) from P2C-1D7 and P5A-3C8, respectively;

iii) from P2C-1D7 and P5A-1D2, respectively;

jjj) from P2C-1D7 and P5A-2F11, respectively;

kkk) from P2B-1A15 and P5A-2E1, respectively;

lll) from P2B-1A1 and P5A-1C8, respectively;

mmm) from P2B-1A10 and P2B-1D9, respectively;

nnn) from P2B-1A10 and P2B-1E4, respectively;

ooo) from P2B-1A10 and P2B-1G1, respectively;

ppp) from P2B-1A10 and P4A-2D9, respectively;

qqq) from P2B-1A10 and P5A-2G7, respectively;

rrr) from P2B-1A10 and P5A-3C8, respectively;

sss) from P2B-1A10 and P5A-1D2, respectively;

ttt) from P2B-1A10 and P5A-2F1 1, respectively;

uuu) from P2B-1A10 and P5A-2E1, respectively;

vvv) from P2B-1A10 and P5A-1C8, respectively;

www) from P2B-1D9 and P2B-1E4, respectively;

xxx) from P2B-1D9 and P2B-1G1, respectively;

yyy) from P2B-1D9 and P4A-2D9, respectively;

zzz) from P2B-1D9 and P5A-2G7, respectively;

aaaa) from P2B-1D9 and P5A-3C8, respectively;

bbbb) from P2B-1D9 and P5A-1D2, respectively;

cccc) from P2B-1D9 and P5A-2F1 1, respectively;

dddd) from P2B-1D9 and P5A-2E1, respectively;

eeee) from P2B-1D9 and P5A-1C8, respectively;

ffff) from P2B-1E4 and P2B-1G1, respectively;

gggg) from P2B-1E4 and P4A-2D9, respectively;

hhhh) from P2B-1E4 and P5A-2G7, respectively;

iiii) from P2B-1E4 and P5A-3C8, respectively;

jjjj) from P2B-1E4 and P5A-1D2, respectively;

kkkk) from P2B-1E4 and P5A-2F1 1, respectively;

llll) from P2B-1E4 and P5A-2E1, respectively;

mmmm) from P2B-1E4 and P5A-1C8, respectively;

nnnn) from P2B-1G1 and P4A-2D9, respectively;

oooo) from P2B-1G1 and P5A-2G7, respectively;

pppp) from P2B-1G1 and P5A-3C8, respectively;

qqqq) from P2B-1G1 and P5A-1D2, respectively;

rrrr) from P2B-1G1 and P5A-2F11, respectively;

ssss) from P2B-1G1 and P5A-2E1, respectively;

tttt) from P2B-1G1 and P5A-1C8, respectively;

uuuu) from P4A-2D9 and P5A-2G7, respectively;

vvvv) from P4A-2D9 and P5A-3C8, respectively;

wwww) from P4A-2D9 and P5A-1D2, respectively;

xxxx) from P4A-2D9 and P5A-2F11, respectively;

yyyy) from P4A-2D9 and P5A-2E1, respectively;

zzzz) from P4A-2D9 and P5A-1C8, respectively;

aaaaa) from P5A-2G7 and P5A-3C8, respectively;

bbbbb) from P5A-2G7 and P5A-1D2, respectively;

ccccc) from P5A-2G7 and P5A-2F11, respectively;

ddddd) from P5A-2G7 and P5A-2E1, respectively;

eeeee) from P5A-2G7 and P5A-1C8, respectively;

fffff) from P5A-3C8 and P5A-1D2, respectively;

ggggg) from P5A-3C8 and P5A-2F11, respectively;

hhhhh) from P5A-3C8 and P5A-2E1, respectively;

iiiii) from P5A-3C8 and P5A-1C8, respectively;

jjjjj) from P5A-1D2 and P5A-2F11, respectively;

kkkkk) from P5A-1D2 and P5A-2E1, respectively;

lllll) from P5A-1D2 and P5A-1C8, respectively;

mmmmm) from P5A-2F11 and P5A-2E1, respectively;

nnnnn) from P5A-2F11 and P5A-1C8, respectively;

ooooo) from P5A-2E1 and P5A-1C8, respectively;

-   49. The antibody or antigen binding fragment of any of the preceding    embodiments, which is a full human antibody.-   50. The antibody or antigen binding fragment of any of the preceding    embodiments, linked to one or more conjugate moieties.-   51. The antibody or antigen binding fragment of embodiment 50,    wherein the conjugate moiety comprises a therapeutic agent, a    radioactive isotope, a detectable label, a pharmacokinetic modifying    moiety, or a purifying moiety, and optionally the conjugate moiety    is covalently attached either directly or via a linker.-   52. An antibody or an antigen-binding fragment thereof, which    competes for binding to RBD of spike protein of SARS-CoV-2 with the    antibody or an antigen-binding fragment thereof of any one of    embodiments 1-44.-   53. An isolated polynucleotide encoding the antibody or antigen    binding fragment of any of the embodiments 1-52.-   54. The isolated polynucleotide of embodiment 53, comprising a    nucleotide sequence selected from a group consisting of: SEQ ID NOs:    9-10, 19-20, 29-30, 39-40, 49-50, 59-60, 63-64, 73-74, 83-84, 93-94,    103-104, 113-114, 144-145, 154-155, 164-165, 174-175, 184-185,    194-195, 204-205, 214-215, 224-225, 234-235, 244-245, 254-255,    264-265, 274-275, 284-285, 294-295, 304-305, 314-315, 324-325,    334-335, 344-345, 354-355, 364-365, 374-375, 384-385, 394-395,    404-405, 414-415, 424-425, and 434-435, or a homologous sequence    thereof having at least 80% sequence identity.-   55. The isolated polynucleotide of embodiment 54, wherein the    homologue sequence encodes the same protein as encoded by any    nucleotide sequence selected from the group consisting of SEQ ID    NOs: 9-10, 19-20, 29-30, 39-40, 49-50, 59-60, 63-64, 73-74, 83-84,    93-94, 103-104, 113-114, 144-145, 154-155, 164-165, 174-175,    184-185, 194-195, 204-205, 214-215, 224-225, 234-235, 244-245,    254-255, 264-265, 274-275, 284-285, 294-295, 304-305, 314-315,    324-325, 334-335, 344-345, 354-355, 364-365, 374-375, 384-385,    394-395, 404-405, 414-415, 424-425, and 434-435.-   56. A vector comprising the isolated polynucleotide of any one of    embodiments 53-55, optionally the vector is an expression vector.-   57. A host cell comprising the vector of embodiment 56.-   58. A pharmaceutical composition comprising the antibody or antigen    binding fragment of any one of embodiments 1-52, and a    pharmaceutically acceptable carrier, or comprising the    polynucleotide of claim 53, and a pharmaceutically acceptable    carrier.-   59. The pharmaceutical composition of embodiment 58, comprising a    combination of two or more antibodies or antigen binding fragments    of any one of embodiments 1-52, and a pharmaceutically acceptable    carrier.-   60. The pharmaceutical composition of embodiment 59, wherein the two    or more antibodies or the antigen binding fragments thereof bind to    different epitopes in RBD of spike protein of SARS-CoV-2.-   61. The pharmaceutical composition of embodiment 60, wherein the two    or more antibodies comprise a first antibody and a second antibody    selected from the group consisting of P2A-1A8, P2A-1A9, P2B-2G11,    P2A-1A10, P2A-1B3, P2B-2F6, P2B-2G4, P2C-1A3, P2C-1C8, P2C-1C10,    P2C-1D5, P2C-1F11, P2B-1G5, P2B-1A1, P2C-1D7, P2B-1A10, P2B-1D9,    P2B- 1E4, P2B-1G1, P4A-2D9, P5A-2G7, P5A-3C8, P5A-1D2, P5A-2F11,    P5A-2E1, P5A-1C8, P1A-1C10, P4A-1H6, P4B-1F4, P5A-1B6, P5A-1B8,    P5A-1B9, P5A-1D1, P5A-1D10, P5A- 2D11, P5A-2G9, P5A-2H3, P5A-3A1,    P5A-3A6, P5A-3B4, P5A-3C12, and P22A-1D1, or an antigen binding    fragment thereof.-   62. The pharmaceutical composition of embodiment 60, wherein the two    or more antibodies comprise a first antibody and a second antibody    selected from the group consisting of P2C-1F11, P2B-2F6, P2B-1G5,    P2B-1A1, P2C-1D7, P2B-1A10, P2B-1D9, P2B-1E4, P2B-1G1, P4A-2D9,    P5A-2G7, P5A-3C8, P5A-1D2, P5A-2F11, P5A-2E1, and P5A-1C8, or an    antigen binding fragment thereof.-   63. The pharmaceutical composition of embodiment 60, wherein the two    or more antibodies comprise a first antibody which comprises    P2C-1F11 or an antigen binding fragment thereof, and a second    antibody which is selected from the group consisting of P2C-1A3,    P2C-1C10, P2B-2F6, P2B-1G5, and P2A-1B3, or an antigen binding    fragment thereof, optionally, the pharmaceutical composition    comprises a first antibody comprising heavy chain CDR sequences and    light chain CDR sequences derived from P2C-1F11, and a second    antibody comprising heavy chain CDR sequences and light chain CDR    sequences derived from antibody P2B-2F6.-   64. The pharmaceutical composition of embodiment 60, wherein the two    or more antibodies comprise a first antibody which comprises P2C-1A3    or an antigen binding fragment thereof, and a second antibody which    is selected from the group consisting of P2C-1F11, and P2A-1B3, or    an antigen binding fragment thereof.-   65. The pharmaceutical composition of embodiment 60, wherein the two    or more antibodies comprise a first antibody which comprises P2B-2F6    or an antigen binding fragment thereof, and a second antibody    selected from the group consisting of P2C-1C10, P2C-1F11, P2B-1G5,    and P2A-1B3, or an antigen binding fragment thereof.-   66. The pharmaceutical composition of embodiment 60, wherein the two    or more antibodies comprise a first antibody which comprises P2A-1B3    or an antigen binding fragment thereof, and a second antibody    selected from the group consisting of P2C-1A3, P2C-1C10, P2C-1F11,    P2B-2F6, and P2A-1A10, or an antigen binding fragment thereof.-   67. A method of producing the antibody or antigen binding fragment    of any of embodiments 1-52 comprising culturing the host cell of    embodiment 57 under the condition at which the vector of embodiment    56 is expressed.-   68. The method of embodiment 67, further comprising purifying the    antibody produced by the host cell.-   69. A kit for detecting a SARS-CoV-2 antigen, comprising the    antibody or antigen binding fragment of any of embodiments 1-52.-   70. The kit of embodiment 69, further comprising a control reagent    comprising RBD of spike protein of the SARS-CoV-2, optionally, the    kit further comprises a set of reagents for detecting complex of the    antibody or the antigen-binding fragment bound to the SARS-CoV-2    antigen.-   71. A method of treating SARS-CoV-2 infection or a disease, disorder    or condition associated with SARs-CoV-2 infection in a subject,    comprising administering a therapeutically effective amount of one    or more of the antibody or antigen binding fragment of any of    embodiments 1-52, or of one or more of the polynucleotides of any    embodiments 53-55, or of one or more of the vectors of embodiment    56, or of the pharmaceutical composition of any of embodiments 58-66    to the subject.-   72. A method of preventing SARS-CoV-2 infection or a disease,    disorder or condition associated with SARs-CoV-2 infection in a    subject, comprising administering a therapeutically effective amount    of one or more of the antibody or antigen binding fragment of any of    embodiments 1-52, or of one or more of the polynucleotides of any    embodiments 53-55, or of one or more of the vectors of embodiment    56, or of the pharmaceutical composition of any of embodiments 58-66    to the subject.-   73. The method of embodiments 71 or 72, wherein the administration    is via oral, nasal, intravenous, subcutaneous, or intramuscular    administration.-   74. The method of embodiment 73, wherein the subject is human.-   75. The method of any of embodiments 71-74, further comprising    administering a therapeutically effective amount of a second    bioactive agent, optionally the second bioactive agent is a    therapeutic agent or a prophylactic agent.-   76. The method of embodiment 75, wherein the therapeutic agent is an    anti-viral agent, optionally, the anti-viral agent comprises an    antiviral peptide, an anti-viral antibody, an anti-viral compound,    an anti-viral cytokine, or an anti-viral oligonucleotide.-   77. A method of detecting presence or amount of SARS-CoV-2 virus    antigen in a sample, comprising contacting the sample with one or    more of the antibody or antigen binding fragment of any of    embodiments 1-52, and determining the presence or the amount of the    SARS-CoV-2 virus antigen in the sample.-   78. Use of one or more of the antibody or antigen binding fragment    of any of embodiments 1-52 in the manufacture of a medicament for    treating SARS-CoV-2 infection or a disease, disorder or condition    associated with SARs-CoV-2 infection.-   79. Use of one or more of the antibody or antigen binding fragment    of any of embodiments 1-52 in the manufacture of a diagnostic    reagent for detecting SARS-CoV-2 infection.-   80. A kit for detecting an antibody capable of specifically binding    to receptor-binding domain (RBD) of the spike protein of SARS-CoV-2,    comprising a polypeptide comprising an amino acid sequence    comprising SEQ ID NO: 128.-   81. The kit of embodiment 80, wherein the polypeptide is immobilized    on a substrate.-   82. The kit of embodiments 81, further comprising a set of reagents    for detecting complex of the antibody bound to the polypeptide.-   83. A method of detecting presence or amount of an antibody capable    of specifically binding to RBD of the spike protein of SARS-CoV-2 in    a sample, comprising contacting the sample with a polypeptide    comprising an amino acid sequence comprising SEQ ID NO: 128, and    determining the presence or the level of the antibody in the sample.-   84. The method of embodiment 83, wherein the absence of the antibody    in the sample or the level of the antibody in the sample being below    a threshold indicates that the subject is more likely to suffer from    disease progression.-   85. A method of determining the likelihood of disease progression in    a subject infected with SARS-CoV-2, the method comprising:    contacting a sample obtained from the subject with a polypeptide    comprising an amino acid sequence comprising SEQ ID NO: 128, and    detecting the presence or the level of an antibody in the sample    wherein the antibody is capable of specifically binding to RBD of    the spike protein of the SARS-CoV-2, wherein the subject is likely    to experience disease progression when the antibody in the sample is    absent or is below a threshold.-   86. A method of monitoring treatment response in a subject infected    with SARS-CoV-2 and received a treatment, the method comprising:

(i) contacting a sample from the subject with a peptide comprising anamino acid sequence comprising SEQ ID NO: 128;

(ii) detecting a first level of an antibody in the sample wherein theantibody is capable of specifically binding to RBD of the spike proteinof the SARS-CoV-2; and

(iii) comparing the first level of the antibody with a second level ofthe antibody detected in the subject prior to the treatment;

wherein the first level being higher than the second level indicatesthat the subject is responsive to the treatment.

-   87. A method of neutralizing SARS-CoV-2 in a subject or in a sample    in vitro, comprising administering a therapeutically effective    amount of one or more of the antibody or antigen binding fragment of    any of embodiments 1-52, or the pharmaceutical composition of any of    claims 58-66 to the subject or to the sample.-   88. A crystal of RBD of the spike protein of SARS-CoV-2 in complex    with an antibody.-   89. The crystal of embodiment 88, having or consisting of a P2₁2₁2₁    space group with unit cell dimensions of a=70.23 Å, b=90.15 Å, and    c=112.35 Å, having or consisting of a C121 space group with unit    cell dimensions of a=194.88 Å, b=85.39 Å, and c=58.51 Å, having or    consisting of a C2 space group with unit cell dimensions of a=193.34    Å, b=86.60 Å, and c=57.16 Å, having or consisting of a C2 space    group with unit cell dimensions of a=158.75 Å, b=67.51 Å, and    c=154.37 Å, or having or consisting of a P2₁2₁2₁ space group with    unit cell dimensions of a=112.54 Å, b=171.57 Å, and c=54.87 Å.-   90. The crystal of embodiment 88, wherein the antibody comprises a    heavy chain variable region of SEQ ID NO: 47 and a light chain    variable region of SEQ ID NO: 48.-   91. The crystal of embodiment 88, wherein the antibody comprises a    heavy chain variable region of SEQ ID NO: 111 and a light chain    variable region of SEQ ID NO: 112.-   92. The crystal of embodiments 88, wherein the antibody comprises a    heavy chain variable region of SEQ ID NO: 432 and a light chain    variable region of SEQ ID NO: 433.-   93. The crystal of embodiments 88, wherein the antibody comprises a    heavy chain variable region of SEQ ID NO: 242 and a light chain    variable region of SEQ ID NO: 243.-   94. The crystal of embodiments 88, wherein the antibody comprises a    heavy chain variable region of SEQ ID NO: 232 and a light chain    variable region of SEQ ID NO: 233.-   95. A computer-implemented method for causing a display of a    graphical three-dimensional representation of the structure of a    portion of a crystal of RBD of the spike protein of SARS-CoV-2 in    complex with an anti-SARS-CoV-2 antibody or an antigen-binding    fragment thereof, wherein the method comprises:

causing said display of said graphical three-dimensional representationby a computer system programmed with instructions for transformingstructure coordinates into said graphical three-dimensionalrepresentation of said structure and for displaying said graphicalthree-dimensional representation,

wherein said graphical three-dimensional representation is generated bytransforming said structure coordinates into said graphicalthree-dimensional representation of said structure,

wherein said structure coordinates comprise structure coordinates of thebackbone atoms of the portion of the crystal,

wherein the portion of the crystal comprises a RBD binding site, and

wherein the crystal has the space group symmetry P2₁2₁2₁ or C121.

-   96. The computer-implemented method of embodiment 95, wherein the    RBD comprises an amino acid sequence as shown in SEQ ID NO: 124, and    the antibody comprises: a) a heavy chain variable region of SEQ ID    NO: 47 and a light chain variable region of SEQ ID NO: 48; or b) a    heavy chain variable region of SEQ ID NO: 111 and a light chain    variable region of SEQ ID NO: 112; or c) a heavy chain variable    region of SEQ ID NO: 432 and a light chain variable region of SEQ ID    NO: 433; or d) a heavy chain variable region of SEQ ID NO: 242 and a    light chain variable region of SEQ ID NO: 243; or e) a heavy chain    variable region of SEQ ID NO: 232 and a light chain variable region    of SEQ ID NO: 233.-   97. The computer-implemented method of embodiment 95, wherein the    structure coordinates comprise the structure coordinates of the    backbone atoms of the amino acid residues corresponding to K444,    G446, G447, N448, Y449, N450, L452, V483, E484, G485, F490 and/or    S494 of the RBD, wherein the residue numbering is according to SEQ    ID NO: 134.-   98. The computer-implemented method of embodiment 95, wherein the    structure coordinates comprise the structure coordinates of the    backbone atoms of the amino acid residues corresponding to Y453,    L455, F456, R457, K458, 5459, N460, Y473, A475, G476, S477, F486,    N487, Y489, Q493, G502, Y505, R403, T415, G416, K417, D420 and/or    Y421 of the RBD, wherein the residue numbering is according to SEQ    ID NO: 134.-   99. The computer-implemented method of embodiment 95, wherein the    structure coordinates comprise the structure coordinates of the    backbone atoms of the amino acid residues corresponding to T415,    G416, K417, D420, Y421, L455, F456, R457, K458, N460, Y473, A475,    G476, S477, F486, N487, Y489 and/or Q493 of the RBD, wherein the    residue numbering is according to SEQ ID NO: 134.-   100. The computer-implemented method of embodiment 95, wherein the    structure coordinates comprise the structure coordinates of the    backbone atoms of the amino acid residues corresponding to T415,    G416, K417, D420, Y421, Y453, L455, F456, R457, K458, N460, Y473,    Q474, A475, G476, S477, N487, Y489, Q493 and/or Y505 of the RBD,    wherein the residue numbering is according to SEQ ID NO: 134.-   101. The computer-implemented method of embodiment 95, wherein the    structure coordinates comprise the structure coordinates of the    backbone atoms of the amino acid residues corresponding to T415,    G416, K417, D420, Y421, Y453, L455, F456, R457, K458, N460, Y473,    A475, G476, S477, F486, N487, Y489 and/or Q493 of the RBD, wherein    the residue numbering is according to SEQ ID NO: 134.-   102. The computer-implemented method of embodiment 95, wherein the    structure coordinates comprise the structure coordinates of the    backbone atoms of the amino acid residues corresponding to T415,    G416, K417, D420, Y421, L455, F456, R457, K458, N460, Y473, Q474,    A475, G476, S477, F486, N487, Y489 and/or Q493 of the RBD, wherein    the residue numbering is according to SEQ ID NO: 134.-   103. A machine-readable data storage medium comprising a data    storage material encoded with machine-readable instructions for:

(a) transforming data into a graphical three-dimensional representationfor the structure of a portion of a crystal of RBD of the spike proteinof SARS-CoV-2 in complex with an anti-SARS-CoV-2 antibody or anantigen-binding fragment thereof; and

(b) causing the display of said graphical three-dimensionalrepresentation;

wherein said data comprise structure coordinates of the backbone atomsof the amino acids defining a RBD binding site; and wherein the crystalor structural homolog has the space group symmetry P2₁2₁2₁ or C121.

-   104. A method of screening for molecules that may be a binding    molecule of RBD of the spike protein of SARS-CoV-2, comprising:

(a) computationally screening agents against a three-dimensional modelto identify potential binding molecules of the RBD;

wherein the three-dimensional model comprises a three-dimensional modelof at least a portion of a crystal of RBD of the spike protein ofSARS-CoV-2 in complex with an anti-SARS-CoV-2 antibody or anantigen-binding fragment thereof;

wherein the three dimensional model is generated from at least a portionof the structure coordinates of the crystal by a computer algorithm forgenerating a three-dimensional model of the crystal useful foridentifying agents that are potential binding molecules of the RBD;wherein the crystal comprises a polypeptide comprising an amino acidsequence SEQ ID NO: 124, and further comprises an antibody comprising:a) a heavy chain variable region of SEQ ID NO: 47 and a light chainvariable region of SEQ ID NO: 48, orb) a heavy chain variable region ofSEQ ID NO: 111 and a light chain variable region of SEQ ID NO: 112; and

wherein the crystal diffracts x-rays for the determination of atomiccoordinates to a resolution of 5 Å or better.

-   105. A method for obtaining structural information about a molecule    or molecular complex comprising applying at least a portion of the    structure coordinates of a RBD of the spike protein of SARS-CoV-2 in    complex with an anti-SARS-CoV-2 antibody or an antigen-binding    fragment thereof, to an X-ray diffraction pattern of the molecule or    molecular complex's crystal structure to cause the generation of a    three-dimensional electron density map of at least a portion of the    molecule or molecular complex;

wherein the crystal comprises a polypeptide comprising an amino acidsequence SEQ ID NO: 124, and further comprises an antibody comprising:a) a heavy chain variable region of SEQ ID NO: 47 and a light chainvariable region of SEQ ID NO: 48, orb) a heavy chain variable region ofSEQ ID NO: 111 and a light chain variable region of SEQ ID NO: 112,

wherein the crystal diffracts x-rays for the determination of atomiccoordinates to a resolution of 5 Å or better.

-   106. Use of a composition comprising a modified antibody or an    antigen-binding fragment thereof and one or more pharmaceutically    acceptable carriers for manufacturing a medicament for treating or    preventing a disease, wherein the composition comprises said    modified antibody or said antigen-binding fragment thereof that    comprises at least an antigen-binding domain having an    antigen-binding affinity and a covalently linked modified human IgG    constant domain, wherein said antigen-binding affinity comprises    SARS-CoV-2 binding affinity, said antigen-binding affinity comprises    at least 50% less or non-detectable binding affinity to SARS-CoV or    MERS-CoV compared to said SARS-CoV-2 binding affinity, and wherein    said modified human IgG constant domain comprises a substitution    with tyrosine at amino acid residue 252, a substitution with    threonine at amino acid residue 254, and a substitution with    glutamic acid at amino acid residue 256, numbered according to the    EU index as in Kabat, said modified antibody has an increased    affinity for FcRn compared to the affinity to FcRn of an antibody    having a wild type human IgG constant domain, and wherein said    disease is caused by said SARS-CoV-2 or related to infection of said    SARS-CoV-2 in said subject.-   107. The use of embodiment 106, wherein said subject is a    symptomatic non-hospitalized adult with COVID-19 caused by    SARS-CoV-2 infection, is aged 60 years and older, is any age having    at least one of the following conditions selected from smoking, has    exogenous or endogenous immunosuppression having HIV infection with    CD4 count <200 cells/mm³, receives corticosteroids equivalent to    prednisone ≥20 mg daily for at least 14 consecutive days within 30    days prior to the treatment, has a treatment with one or more    biologics therapeutical agents, one or more immunomodulators, cancer    chemotherapy within 90 days prior to the treatment; has chronic lung    disease, chronic asthma; obesity with body mass index [BMI]>35,    symptoms of COVID-19 selected from fever, cough, sore throat,    malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of    taste and smell, or a combination thereof, has shortness of breath,    dyspnea, or abnormal chest imaging, having evidence of lower    respiratory disease during clinical assessment or imaging, has    saturation of oxygen (SpO2) ≥94% on room air at sea level, has    severe symptoms of the infection of said SARS-CoV-2, having SpO2    <94% on room air at sea level, having a ratio of arterial partial    pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300    mmHg, respiratory frequency>30 breaths per minute, lung    infiltrates >50%, active symptoms of antibody-dependent enhancement    (ADE), a history of antibody-dependent enhancement (ADE), being    allergic to an antibody treatment, being a hospital inpatient    requiring supportive management of complications of severe infection    of said SARS-CoV-2 selected from pneumonia, has hypoxemic    respiratory failure/ARDS, sepsis and septic shock, cardiomyopathy    and arrhythmia, acute kidney injury, and complications from    prolonged hospitalization, including secondary bacterial and fungal    infections, thromboembolism, gastrointestinal bleeding, critical    illness polyneuropathy/myopathy, or a combination thereof.

REFERENCES

-   1 Li, Q. et al. N Engl J Med, 10.1056/NEJMoa2001316,    doi:10.1056NEJMoa2001316 (2020).-   2 Zhou, P. et al. A pneumonia outbreak associated with a new    coronavirus of probable bat origin. Nature 579, 270-273,    doi:10.1038/s41586-020-2012-7 (2020).-   3 Zhu, N. et al., 2019. N Engl J Med 382, 727-733,    doi:10.1056/NEJMoa2001017 (2020).-   4 Wu, F. et al., Nature 579, 265-269, doi:10.1038/s41586-020-2008-3    (2020).-   5 Chan, J. F.-W. et al. A familial cluster of pneumonia associated    with the 2019 novel coronavirus indicating person-to-person    transmission: a study of a family cluster. Lancet 395, 514-523,    doi:10.1016/S0140-6736(20)30154-9 (2020).-   6 Guan, W.-J. et al., N Engl J Med, 10.1056/NEJMoa2002032,    doi:10.1056/NEJMoa2002032 (2020).-   7 Huang, C. et al., Lancet 395, 497-506,    doi:10.1016/S0140-6736(20)30183-5 (2020).-   8 Wang, D. et al., JAMA, e201585, doi:10.1001/jama.2020.1585 (2020).-   9 Chinazzi, M. et al. The effect of travel restrictions on the    spread of the 2019 novel coronavirus (COVID-19) outbreak. Science,    eaba9757, doi:10.1126/science.aba9757 (2020).-   10 Lu, R. et al. Genomic characterisation and epidemiology of 2019    novel coronavirus: implications for virus origins and receptor    binding. Lancet 395, 565-574, doi:10.1016/S0140-6736(20)30251-8    (2020).-   11 Wu, A. et al., Cell Host Microbe, S1931-3128(1920)30072-X,    doi:10.1016/j.chom.2020.02.001 (2020).-   12 Ge, X.-Y. et al. Isolation and characterization of a bat    SARS-like coronavirus that uses the ACE2 receptor. Nature 503,    535-538, doi:10.1038/nature12711 (2013).-   13 Hoffmann, M. et al. SARS-CoV-2 Cell Entry Depends on ACE2 and    TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.    Cell, S0092-8674(0020)30229-30224, doi:10.1016/j.cell.2020.02.052    (2020).-   14 Walls, A. C. et al. Structure, Function, and Antigenicity of the    SARS-CoV-2 Spike Glycoprotein. Cell, S0092-8674(0020)30262-30262,    doi:10.1016/j.cell.2020.02.058 (2020).-   15 Du, L. et al. The spike protein of SARS-CoV—a target for vaccine    and therapeutic development. Nat Rev Microbiol 7, 226-236,    doi:10.1038/nrmicro2090 (2009).-   16 Li, F. Structure, Function, and Evolution of Coronavirus Spike    Proteins. Annu Rev Virol 3, 237-261,    doi:10.1146/annurev-virology-110615-042301 (2016).-   17 Wrapp, D. et al. Cryo-EM structure of the 2019-nCoV spike in the    prefusion conformation. Science, eabb2507,    doi:10.1126/science.abb2507 (2020).-   18 Gui, M. et al. Cryo-electron microscopy structures of the    SARS-CoV spike glycoprotein reveal a prerequisite conformational    state for receptor binding. Cell Res 27, 119-129,    doi:10.1038/cr.2016.152 (2017).-   19 Song, W., Gui, M., Wang, X. & Xiang, Y. Cryo-EM structure of the    SARS coronavirus spike glycoprotein in complex with its host cell    receptor ACE2. PLoS Pathog 14, e1007236-e1007236,    doi:10.1371/journal.ppat.1007236 (2018).-   20 Kirchdoerfer, R. N. et al. Stabilized coronavirus spikes are    resistant 725 to conformational changes induced by receptor    recognition or proteolysis. Sci Rep 8, 15701-15701,    doi:10.1038/s41598-018-34171-7 (2018).-   21 Yuan, Y. et al. Cryo-EM structures of MERS-CoV and SARS-CoV spike    glycoproteins reveal the dynamic receptor binding domains. Nat    Commun 8, 15092-15092, doi:10.1038/ncomms15092 (2017).-   22 Wan, Y., Shang, J., Graham, R., Baric, R. S. & Li, F, J Virol,    JVI.00127-00120, doi:10.1128/JVI.00127-20 (2020).-   23 Kruse, R. L., F1000Res 9, 72-72,    doi:10.12688/f1000research.22211.2 (2020).-   24 Li, W. et al. Angiotensin-converting enzyme 2 is a functional    receptor for the SARS coronavirus. Nature 426, 450-454,    doi:10.1038/nature02145 (2003).-   25 Hamming, I. et al. The emerging role of ACE2 in physiology and    disease. J Pathol 212, 1-11, doi:10.1002/path.2162 (2007).-   26 Xu, J. et al. Antibodies and vaccines against Middle East    respiratory syndrome coronavirus. Emerg Microbes Infect 8, 841-856,    doi:10.1080/22221751.2019.1624482 (2019).-   27 Sanders, R. W. et al. Stabilization of the soluble, cleaved,    trimeric form of the envelope glycoprotein complex of human    immunodeficiency virus type 1. J Virol 76, 8875-8889,    doi:10.1128/jvi.76.17.8875-8889.2002 (2002).-   28 Kong, L. et al. Key gp120 Glycans Pose Roadblocks to the Rapid    Development of VRC01-Class Antibodies in an HIV-1-Infected Chinese    Donor. Immunity 44, 939-950,doi:10.1016/j.immuni.2016.03.006 (2016).-   29 Liao, H.-X. et al. High-throughput isolation of immunoglobulin    genes from single human B cells and expression as monoclonal    antibodies. J Virol Methods 158, 171-179,    doi:10.1016/jjviromet.2009.02.014 (2009).-   30 Yu, L. et al. Delineating antibody recognition against Zika virus    during natural infection. JCI Insight 2, e93042,    doi:10.1172/jci.insight.93042 (2017).-   31 Corti, D. & Lanzavecchia, A. Broadly neutralizing antiviral    antibodies. Annu Rev Immunol 31, 705-742,    doi:10.1146/annurev-immunol-032712-095916 (2013).-   32 Stettler, K. et al. Specificity, cross-reactivity, and function    of antibodies elicited by Zika virus infection. Science 353,    823-826, doi:10.1126/science.aaf8505 (2016).-   33 Scheid, J. F. et al. Broad diversity of neutralizing antibodies    isolated from memory B cells in HIV-infected individuals. Nature    458, 636-640, doi:10.1038/nature07930 (2009).-   34 Wu, X. et al. Focused evolution of HIV-1 neutralizing antibodies    revealed by structures and deep sequencing. Science 333, 1593-1602,    doi:10.1126/science.1207532 (2011).-   35 Liao, H.-X. et al. Co-evolution of a broadly neutralizing HIV-1    antibody and founder virus. Nature 496, 469-476,    doi:10.1038/nature12053 (2013).-   36. Yuan, M. et al. A highly conserved cryptic epitope in the    receptor-binding domains of SARS-CoV-2 and SARS-CoV. Science,    doi:10.1126/science.abb7269 (2020).-   37. Pinto, D. et al. Structural and functional analysis of a potent    sarbecovirus neutralizing 1 antibody. BioRxiv (2020).-   38 Tian, X. et al. Potent binding of 2019 novel coronavirus spike    protein by a SARS coronavirus-specific human monoclonal antibody.    Emerg Microbes Infect 9, 382-385,doi:10.1080/22221751.2020.1729069    (2020).-   39 Wang, N. et al. Structure of MERS-CoV spike receptor-binding    domain complexed with human receptor DPP4. Cell Res 23, 986-993,    doi:10.1038/cr.2013.92 (2013).-   40 Jiang, L. et al. Potent neutralization of MERS-CoV by human    neutralizing monoclonal antibodies to the viral spike glycoprotein.    Sci Transl Med 6, 234ra259-234ra259,    doi:10.1126/scitranslmed.3008140 (2014).-   41 Zhang, S. et al. Structural Definition of a Unique Neutralization    774 Epitope on the Receptor-Binding Domain of MERS-CoV Spike    Glycoprotein. Cell Rep 24, 441-452, doi:10.1016/j.celrep.2018.06.041    (2018).-   42 Wu, X. et al. Rational design of envelope identifies broadly    neutralizing human monoclonal antibodies to HIV-1. Science 329,    856-861, doi:10.1126/science.1187659 779 (2010).-   43 Tiller, T. et al. Efficient generation of monoclonal antibodies    from single human B cells by single cell RT-PCR and expression    vector cloning. J Immunol Methods 329, 112-124, doi:10.1016/    /j.jim.2007.09.017 (2008).-   44 Zhu, Z. et al. Potent cross-reactive neutralization of SARS    coronavirus isolates by human monoclonal antibodies. Proc NatlAcad    Sci USA 104, 12123-12128,doi:10.1073/pnas.0701000104 (2007).-   45 Niu, P. et al. Ultrapotent Human Neutralizing Antibody    Repertoires Against MiddleEast Respiratory Syndrome Coronavirus From    a Recovered Patient. J Infect Dis218, 1249-1260,    doi:10.1093/infdis/jiy311 (2018).-   46 Jia, W. et al. Single intranasal immunization with chimpanzee    adenovirus-based vaccine induces sustained and protective immunity    against MERS-CoV infection. Emerg Microbes Infect8, 760-772,    doi:10.1080/22221751.2019.1620083 (2019).-   47 Zhang, L. et al. Antibody responses against SARS coronavirus are    correlated with disease outcome of infected individuals. J Med    Viro178, 1-8, doi:10.1002/jmv.20499(2006).-   48 Zhang, Q. et al. Potent neutralizing monoclonal antibodies    against Ebola virus infection. Sci Rep 6, 25856-25856,    doi:10.1038/srep25856 (2016).-   49. McCoy, A. J. et al. Phaser crystallographic software. Journal of    applied crystallography 40, 658-674, doi:10.1107/s0021889807021206    (2007).-   50. Cohen, S. X. et al. ARP/wARP and molecular replacement: the next    generation. Acta crystallographica. Section D, Biological    crystallography 64, 49-60, doi:10.1107/s0907444907047580 (2008).-   51 Emsley, P. & Cowtan, K. Coot: model-building tools for molecular    graphics. Acta crystallographica. Section D, Biological    crystallography 60, 2126-2132, doi:10.1107/s0907444904019158 (2004).-   52 Adams, P. D. et al. PHENIX: building new software for automated    crystallographic structure determination. Acta crystallographica.    Section D, Biological crystallography 58, 1948-1954,    doi:10.1107/s0907444902016657 (2002).-   53 Janson, G., Zhang, C., Prado, M. G. & Paiardini, A. PyMod 2.0:    improvements in protein sequence-structure analysis and homology    modeling within PyMOL. Bioinformatics (Oxford, England) 33, 444-446,    doi:10.1093/bioinformatics/btw638 (2017).-   54 Arentz, G., Thurgood, L. A., Lindop, R., Chataway, T. K., and    Gordon, T. P. (2012). Secreted human Ro52 autoantibody proteomes    express a restricted set of public clonotypes. Journal of    autoimmunity 39, 466-470.-   55 Barnes, C. O., West, A. P., Jr., Huey-Tubman, K. E.,    Hoffmann, M. A. G., Sharaf, N. G., Hoffman, P. R., Koranda, N.,    Gristick, H. B., Gaebler, C., Muecksch, F., et al. (2020).    Structures of human antibodies bound to SARS-CoV-2 spike reveal    common epitopes and recurrent features of antibodies. bioRxiv.-   56 Baum, A., Fulton, B. O., Wloga, E., Copin, R., Pascal, K. E.,    Russo, V., Giordano, S., Lanza, K., Negron, N., Ni, M., et al.    (2020). Antibody cocktail to SARS-CoV-2 spike protein prevents rapid    mutational escape seen with individual antibodies. Science.-   57 Brouwer, P. J. M., Caniels, T. G., van der Straten, K.,    Snitselaar, J. L., Aldon, Y., Bangaru, S., Torres, J. L.,    Okba, N. M. A., Claireaux, M., Kerster, G., et al. (2020). Potent    neutralizing antibodies from COVID-19 patients define multiple    targets of vulnerability. Science.-   58 Cao, Y., Su, B., Guo, X., Sun, W., Deng, Y., Bao, L., Zhu, Q.,    Zhang, X., Zheng, Y., Geng, C., et al. (2020). Potent neutralizing    antibodies against SARS-CoV-2 identified by high-throughput    single-cell sequencing of convalescent patients' B cells. Cell.-   59 Chi, X., Yan, R., Zhang, J., Zhang, G., Zhang, Y., Hao, M.,    Zhang, Z., Fan, P., Dong, Y., Yang, Y., et al. (2020). A    neutralizing human antibody binds to the N-terminal domain of the    Spike protein of SARS-CoV-2. Science.-   60 Hansen, J., Baum, A., Pascal, K. E., Russo, V., Giordano, S.,    Wloga, E., Fulton, B. O., Yan, Y., Koon, K., Patel, K., et al.    (2020). Studies in humanized mice and convalescent humans yield a    SARS-CoV-2 antibody cocktail. Science.-   61 Henry Dunand, C. J., and Wilson, P. C. (2015). Restricted,    canonical, stereotyped and convergent immunoglobulin responses.    Philos Trans R Soc Lond B Biol Sci 370.-   62 Jackson, K. J., Liu, Y., Roskin, K. M., Glanville, J., Hoh, R.    A., Seo, K., Marshall, E. L., Gurley, T. C., Moody, M. A.,    Haynes, B. F., et al. (2014). Human responses to influenza    vaccination show seroconversion signatures and convergent antibody    rearrangements. Cell host & microbe 16, 105-114.-   63 Ju, B., Zhang, Q., Ge, J., Wang, R., Sun, J., Ge, X., Yu, J.,    Shan, S., Zhou, B., Song, S., et al. (2020). Human neutralizing    antibodies elicited by SARS-CoV-2 infection. Nature.-   64 Lan, J., Ge, J., Yu, J., Shan, S., Zhou, H., Fan, S., Zhang, Q.,    Shi, X., Wang, Q., Zhang, L., and Wang, X. (2020). Structure of the    SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor.    Nature 581, 215-220.-   65 Liu, L., Wang, P., Nair, M. S., Yu, J., Huang, Y., Rapp, M. A.,    Wang, Q., Luo, Y., Sahi, V., Figueroa, A., et al. (2020). Potent    Neutralizing Monoclonal Antibodies Directed to Multiple Epitopes on    the SARS-CoV-2 Spike. bioRxiv.-   66 Lv, H., Wu, N. C., Tsang, O. T., Yuan, M., Perera, R., Leung, W.    S., So, R. T. Y., Chan, J. M. C., Yip, G. K., Chik, T. S. H., et al.    (2020). Cross-reactive antibody response between SARS-CoV-2 and    SARS-CoV infections. bioRxiv.-   67 Parameswaran, P., Liu, Y., Roskin, K. M., Jackson, K. K.,    Dixit, V. P., Lee, J. Y., Artiles, K. L., Zompi, S., Vargas, M. J.,    Simen, B. B., et al. (2013). Convergent antibody signatures in human    dengue. Cell host & microbe 13, 691-700.-   68 Pieper, K., Tan, J., Piccoli, L., Foglierini, M., Barbieri, S.,    Chen, Y., Silacci-Fregni, C., Wolf, T., Jarrossay, D., Anderle, M.,    et al. (2017). Public antibodies to malaria antigens generated by    two LAIR1 insertion modalities. Nature 548, 597-601.-   69 Pinto, D., Park, Y. J., Beltramello, M., Walls, A. C.,    Tortorici, M. A., Bianchi, S., Jaconi, S., Culap, K., Zatta, F., De    Marco, A., et al. (2020). Cross-neutralization of SARS-CoV-2 by a    human monoclonal SARS-CoV antibody. Nature.-   70 Ravichandran, S., Coyle, E. M., Klenow, L., Tang, J., Grubbs, G.,    Liu, S., Wang, T., Golding, H., and Khurana, S. (2020). Antibody    signature induced by SARS-CoV-2 spike protein immunogens in rabbits.    Sci Transl Med 12.-   71 Robbiani, D. F., Gaebler, C., Muecksch, F., Lorenzi, J. C. C.,    Wang, Z., Cho, A., Agudelo, M., Barnes, C. O., Gazumyan, A., Finkin,    S., et al. (2020). Convergent antibody responses to SARS-CoV-2 in    convalescent individuals. Nature.-   72 Rogers, T. F., Zhao, F., Huang, D., Beutler, N., Burns, A.,    He, W. T., Limbo, O., Smith, C., Song, G., Woehl, J., et al. (2020).    Isolation of potent SARS-CoV-2 neutralizing antibodies and    protection from disease in a small animal model. Science.-   73 Setliff, I., McDonnell, W. J., Raju, N., Bombardi, R. G.,    Murji, A. A., Scheepers, C., Ziki, R., Mynhardt, C., Shepherd, B.    E., Mamchak, A. A., et al. (2018). Multi-Donor Longitudinal Antibody    Repertoire Sequencing Reveals the Existence of Public Antibody    Clonotypes in HIV-1 Infection. Cell host & microbe 23, 845-854.e846.-   74 Seydoux, E., Homad, L. J., MacCamy, A. J., Parks, K. R.,    Hurlburt, N. K., Jennewein, M. F., Akins, N. R., Stuart, A. B.,    Wan, Y. H., Feng, J., et al. (2020). Analysis of a    SARS-CoV-2-Infected Individual Reveals Development of Potent    Neutralizing Antibodies with Limited Somatic Mutation. Immunity.-   75 Shang, J., Ye, G., Shi, K., Wan, Y., Luo, C., Aihara, H., Geng,    Q., Auerbach, A., and Li, F. (2020). Structural basis of receptor    recognition by SARS-CoV-2. Nature 581, 221-224.-   76 Trück, J., Ramasamy, M. N., Galson, J. D., Rance, R., Parkhill,    J., Lunter, G., Pollard, A. J., and Kelly, D. F. (2015).    Identification of antigen-specific B cell receptor sequences using    public repertoire analysis. Journal of immunology (Baltimore,    Md.: 1950) 194, 252-261-   77 Wang, C., Li, W., Drabek, D., Okba, N. M. A., van Haperen, R.,    Osterhaus, A., van Kuppeveld, F. J. M., Haagmans, B. L., Grosveld,    F., and Bosch, B. J. (2020). A human monoclonal antibody blocking    SARS-CoV-2 infection. Nat Commun 11, 2251.-   78 Wec, A. Z., Wrapp, D., Herbert, A. S., Maurer, D. P., Haslwanter,    D., Sakharkar, M., Jangra, R. K., Dieterle, M. E., Lilov, A., Huang,    D., et al. (2020). Broad neutralization of SARS-related viruses by    human monoclonal antibodies. Science.-   79 Wu, Y., Wang, F., Shen, C., Peng, W., Li, D., Zhao, C., Li, Z.,    Li, S., Bi, Y., Yang, Y., et al. (2020). A noncompeting pair of    human neutralizing antibodies block COVID-19 virus binding to its    receptor ACE2. Science 368, 1274-1278.-   80 Yan, R., Zhang, Y., Li, Y., Xia, L., Guo, Y., and Zhou, Q.    (2020). Structural basis for the recognition of SARS-CoV-2 by    full-length human ACE2. Science 367, 1444-1448.-   81 Yuan, M., Liu, H., Wu, N.C., Lee, C. D., Zhu, X., Zhao, F.,    Huang, D., Yu, W., Hua, Y., Tien, H., et al. (2020). Structural    basis of a public antibody response to SARS-CoV-2. bioRxiv.-   82 Zost, S. J., Gilchuk, P., Case, J. B., Binshtein, E., Chen, R.    E., Reidy, J. X., Trivette, A., Nargi, R. S., Sutton, R. E.,    Suryadevara, N., et al. (2020). Potently neutralizing human    antibodies that block SARS-CoV-2 receptor binding and protect    animals. bioRxiv.-   83 Dall'Acqua, W. F., P. A. Kiener, and H. Wu. 2006. ‘Properties of    human IgG1s engineered for enhanced binding to the neonatal Fc    receptor (FcRn)’, J Biol Chem, 281: 23514-24.

1-34. (canceled)
 35. An antibody or an antigen-binding fragment thereofhaving specific binding affinity to receptor binding domain (RBD) ofspike protein of SARS-CoV-2, wherein said antibody or antigen-bindingdomain comprises: a. a heavy chain CDR1 (HCDR1) comprising the sequenceof SEQ ID NO: 1, a heavy chain CDR2 (HCDR2) comprising the sequence ofSEQ ID NO: 2, a heavy chain CDR3 (HCDR3) comprising the sequence of SEQID NO: 3; a light chain CDR1 (LCDR1) comprising the sequence of SEQ IDNO: 4, a light chain CDR2 (LCDR2) comprising the sequence of SEQ ID NO:5, and a light chain CDR3 (LCDR3) comprising the sequence of SEQ ID NO:6; b. a HCDR1 comprising the sequence of SEQ ID NO: 11, a HCDR2comprising the sequence of SEQ ID NO: 12, a HCDR3 comprising thesequence of SEQ ID NO: 13, a LCDR1 comprising the sequence of SEQ ID NO:14, a LCDR2 comprising the sequence of SEQ ID NO: 15, and a LCDR3comprising the sequence of SEQ ID NO: 16; c. a HCDR1 comprising thesequence of SEQ ID NO: 21, a HCDR2 comprising the sequence of SEQ ID NO:22, a HCDR3 comprising the sequence of SEQ ID NO: 23, a LCDR1 comprisingthe sequence of SEQ ID NO: 24, a LCDR2 comprising the sequence of SEQ IDNO: 25, and a LCDR3 comprising the sequence of SEQ ID NO: 26; d. a HCDR1comprising the sequence of SEQ ID NO: 31, a HCDR2 comprising thesequence of SEQ ID NO: 32, a HCDR3 comprising the sequence of SEQ ID NO:33, a LCDR1 comprising the sequence of SEQ ID NO: 34, a LCDR2 comprisingthe sequence of SEQ ID NO: 35, and a LCDR3 comprising the sequence ofSEQ ID NO: 36; e. a HCDR1 comprising the sequence of SEQ ID NO: 41, aHCDR2 comprising the sequence of SEQ ID NO: 42, a HCDR3 comprising thesequence of SEQ ID NO: 43, a LCDR1 comprising the sequence of SEQ ID NO:44, a LCDR2 comprising the sequence of SEQ ID NO: 45, and a LCDR3comprising the sequence of SEQ ID NO: 46; f. a HCDR1 comprising thesequence of SEQ ID NO: 51, a HCDR2 comprising the sequence of SEQ ID NO:52, a HCDR3 comprising the sequence of SEQ ID NO: 53, a LCDR1 comprisingthe sequence of SEQ ID NO: 54, a LCDR2 comprising the sequence of SEQ IDNO: 55, and a LCDR3 comprising the sequence of SEQ ID NO: 56; g. a HCDR1comprising the sequence of SEQ ID NO: 65, a HCDR2 comprising thesequence of SEQ ID NO: 66, a HCDR3 comprising the sequence of SEQ ID NO:67, a LCDR1 comprising the sequence of SEQ ID NO: 68, a LCDR2 comprisingthe sequence of SEQ ID NO: 69, and a LCDR3 comprising the sequence ofSEQ ID NO: 70; h. a HCDR1 comprising the sequence of SEQ ID NO: 75, aHCDR2 comprising the sequence of SEQ ID NO: 76, a HCDR3 comprising thesequence of SEQ ID NO: 77, a LCDR1 comprising the sequence of SEQ ID NO:78, a LCDR2 comprising the sequence of SEQ ID NO: 79, and a LCDR3comprising the sequence of SEQ ID NO: 80; i. a HCDR1 comprising thesequence of SEQ ID NO: 85, a HCDR2 comprising the sequence of SEQ ID NO:86, a HCDR3 comprising the sequence of SEQ ID NO: 87, a LCDR1 comprisingthe sequence of SEQ ID NO: 88, a LCDR2 comprising the sequence of SEQ IDNO: 89, and a LCDR3 comprising the sequence of SEQ ID NO: 90; j. a HCDR1comprising the sequence of SEQ ID NO: 95, a HCDR2 comprising thesequence of SEQ ID NO: 96, a HCDR3 comprising the sequence of SEQ ID NO:97, a LCDR1 comprising the sequence of SEQ ID NO: 98, a LCDR2 comprisingthe sequence of SEQ ID NO: 99, and a LCDR3 comprising the sequence ofSEQ ID NO: 100; k. a HCDR1 comprising the sequence of SEQ ID NO: 105, aHCDR2 comprising the sequence of SEQ ID NO: 106, a HCDR3 comprising thesequence of SEQ ID NO: 107, a LCDR1 comprising the sequence of SEQ IDNO: 108, a LCDR2 comprising the sequence of SEQ ID NO: 109, and a LCDR3comprising the sequence of SEQ ID NO: 110; l. a HCDR1 comprising thesequence of SEQ ID NO: 136, a HCDR2 comprising the sequence of SEQ IDNO: 137, a HCDR3 comprising the sequence of SEQ ID NO: 138, a LCDR1comprising the sequence of SEQ ID NO: 139, a LCDR2 comprising thesequence of SEQ ID NO: 140, and a LCDR3 comprising the sequence of SEQID NO: 141; m. HCDR1 comprising the sequence of SEQ ID NO: 146, a HCDR2comprising the sequence of SEQ ID NO: 147, a HCDR3 comprising thesequence of SEQ ID NO: 148, a LCDR1 comprising the sequence of SEQ IDNO: 149, a LCDR2 comprising the sequence of SEQ ID NO: 150, and a LCDR3comprising the sequence of SEQ ID NO: 151; n. HCDR1 comprising thesequence of SEQ ID NO: 156, a HCDR2 comprising the sequence of SEQ IDNO: 157, a HCDR3 comprising the sequence of SEQ ID NO: 158, a LCDR1comprising the sequence of SEQ ID NO: 159, a LCDR2 comprising thesequence of SEQ ID NO: 160, and a LCDR3 comprising the sequence of SEQID NO: 161; o. HCDR1 comprising the sequence of SEQ ID NO: 166, a HCDR2comprising the sequence of SEQ ID NO: 167, a HCDR3 comprising thesequence of SEQ ID NO: 168, a LCDR1 comprising the sequence of SEQ IDNO: 169, a LCDR2 comprising the sequence of SEQ ID NO: 170, and a LCDR3comprising the sequence of SEQ ID NO: 171; p. HCDR1 comprising thesequence of SEQ ID NO: 176, a HCDR2 comprising the sequence of SEQ IDNO: 177, a HCDR3 comprising the sequence of SEQ ID NO: 178, a LCDR1comprising the sequence of SEQ ID NO: 179, a LCDR2 comprising thesequence of SEQ ID NO: 180, and a LCDR3 comprising the sequence of SEQID NO: 181; q. HCDR1 comprising the sequence of SEQ ID NO: 186, a HCDR2comprising the sequence of SEQ ID NO: 187, a HCDR3 comprising thesequence of SEQ ID NO: 188, a LCDR1 comprising the sequence of SEQ IDNO: 189, a LCDR2 comprising the sequence of SEQ ID NO: 190, and a LCDR3comprising the sequence of SEQ ID NO: 191; r. HCDR1 comprising thesequence of SEQ ID NO: 196, a HCDR2 comprising the sequence of SEQ IDNO: 197, a HCDR3 comprising the sequence of SEQ ID NO: 198, a LCDR1comprising the sequence of SEQ ID NO: 199, a LCDR2 comprising thesequence of SEQ ID NO: 200, and a LCDR3 comprising the sequence of SEQID NO: 201; s. HCDR1 comprising the sequence of SEQ ID NO: 206, a HCDR2comprising the sequence of SEQ ID NO: 207, a HCDR3 comprising thesequence of SEQ ID NO: 208, a LCDR1 comprising the sequence of SEQ IDNO: 209, a LCDR2 comprising the sequence of SEQ ID NO: 210, and a LCDR3comprising the sequence of SEQ ID NO: 211; t. HCDR1 comprising thesequence of SEQ ID NO: 216, a HCDR2 comprising the sequence of SEQ IDNO: 217, a HCDR3 comprising the sequence of SEQ ID NO: 218, a LCDR1comprising the sequence of SEQ ID NO: 219, a LCDR2 comprising thesequence of SEQ ID NO: 220, and a LCDR3 comprising the sequence of SEQID NO: 221; u. HCDR1 comprising the sequence of SEQ ID NO: 226, a HCDR2comprising the sequence of SEQ ID NO: 227, a HCDR3 comprising thesequence of SEQ ID NO: 228, a LCDR1 comprising the sequence of SEQ IDNO: 229, a LCDR2 comprising the sequence of SEQ ID NO: 230, and a LCDR3comprising the sequence of SEQ ID NO: 231; v. HCDR1 comprising thesequence of SEQ ID NO: 236, a HCDR2 comprising the sequence of SEQ IDNO: 237, a HCDR3 comprising the sequence of SEQ ID NO: 238, a LCDR1comprising the sequence of SEQ ID NO: 239, a LCDR2 comprising thesequence of SEQ ID NO: 240, and a LCDR3 comprising the sequence of SEQID NO: 241; w. HCDR1 comprising the sequence of SEQ ID NO: 246, a HCDR2comprising the sequence of SEQ ID NO: 247, a HCDR3 comprising thesequence of SEQ ID NO: 248, a LCDR1 comprising the sequence of SEQ IDNO: 249, a LCDR2 comprising the sequence of SEQ ID NO: 250, and a LCDR3comprising the sequence of SEQ ID NO: 251; x. HCDR1 comprising thesequence of SEQ ID NO: 256, a HCDR2 comprising the sequence of SEQ IDNO: 257, a HCDR3 comprising the sequence of SEQ ID NO: 258, a LCDR1comprising the sequence of SEQ ID NO: 259, a LCDR2 comprising thesequence of SEQ ID NO: 260, and a LCDR3 comprising the sequence of SEQID NO: 261; y. HCDR1 comprising the sequence of SEQ ID NO: 266, a HCDR2comprising the sequence of SEQ ID NO: 267, a HCDR3 comprising thesequence of SEQ ID NO: 268, a LCDR1 comprising the sequence of SEQ IDNO: 269, a LCDR2 comprising the sequence of SEQ ID NO: 270, and a LCDR3comprising the sequence of SEQ ID NO: 271; z. HCDR1 comprising thesequence of SEQ ID NO: 276, a HCDR2 comprising the sequence of SEQ IDNO: 277, a HCDR3 comprising the sequence of SEQ ID NO: 278, a LCDR1comprising the sequence of SEQ ID NO: 279, a LCDR2 comprising thesequence of SEQ ID NO: 280, a LCDR3 comprising the sequence of SEQ IDNO: 281; aa. HCDR1 comprising the sequence of SEQ ID NO: 286, a HCDR2comprising the sequence of SEQ ID NO: 287, a HCDR3 comprising thesequence of SEQ ID NO: 288, a LCDR1 comprising the sequence of SEQ IDNO: 289, a LCDR2 comprising the sequence of SEQ ID NO: 290, a LCDR3comprising the sequence of SEQ ID NO: 291; bb. HCDR1 comprising thesequence of SEQ ID NO: 296, a HCDR2 comprising the sequence of SEQ IDNO: 297, a HCDR3 comprising the sequence of SEQ ID NO: 298, a LCDR1comprising the sequence of SEQ ID NO: 299, a LCDR2 comprising thesequence of SEQ ID NO: 300, a LCDR3 comprising the sequence of SEQ IDNO: 301; cc. HCDR1 comprising the sequence of SEQ ID NO: 306, a HCDR2comprising the sequence of SEQ ID NO: 307, a HCDR3 comprising thesequence of SEQ ID NO: 308, a LCDR1 comprising the sequence of SEQ IDNO: 309, a LCDR2 comprising the sequence of SEQ ID NO: 310, a LCDR3comprising the sequence of SEQ ID NO: 311; dd. HCDR1 comprising thesequence of SEQ ID NO: 316, a HCDR2 comprising the sequence of SEQ IDNO: 317, a HCDR3 comprising the sequence of SEQ ID NO: 318, a LCDR1comprising the sequence of SEQ ID NO: 319, a LCDR2 comprising thesequence of SEQ ID NO: 320, a LCDR3 comprising the sequence of SEQ IDNO: 321; ee. HCDR1 comprising the sequence of SEQ ID NO: 326, a HCDR2comprising the sequence of SEQ ID NO: 327, a HCDR3 comprising thesequence of SEQ ID NO: 328, a LCDR1 comprising the sequence of SEQ IDNO: 329, a LCDR2 comprising the sequence of SEQ ID NO: 330, a LCDR3comprising the sequence of SEQ ID NO: 331; ff. HCDR1 comprising thesequence of SEQ ID NO: 336, a HCDR2 comprising the sequence of SEQ IDNO: 337, a HCDR3 comprising the sequence of SEQ ID NO: 338, a LCDR1comprising the sequence of SEQ ID NO: 339, a LCDR2 comprising thesequence of SEQ ID NO: 340, a LCDR3 comprising the sequence of SEQ IDNO: 341; gg. HCDR1 comprising the sequence of SEQ ID NO: 346, a HCDR2comprising the sequence of SEQ ID NO: 347, a HCDR3 comprising thesequence of SEQ ID NO: 348, a LCDR1 comprising the sequence of SEQ IDNO: 349, a LCDR2 comprising the sequence of SEQ ID NO: 350, a LCDR3comprising the sequence of SEQ ID NO: 351; hh. HCDR1 comprising thesequence of SEQ ID NO: 356, a HCDR2 comprising the sequence of SEQ IDNO: 357, a HCDR3 comprising the sequence of SEQ ID NO: 358, a LCDR1comprising the sequence of SEQ ID NO: 359, a LCDR2 comprising thesequence of SEQ ID NO: 360, a LCDR3 comprising the sequence of SEQ IDNO: 361; ii. HCDR1 comprising the sequence of SEQ ID NO: 366, a HCDR2comprising the sequence of SEQ ID NO: 367, a HCDR3 comprising thesequence of SEQ ID NO: 368, a LCDR1 comprising the sequence of SEQ IDNO: 369, a LCDR2 comprising the sequence of SEQ ID NO: 370, a LCDR3comprising the sequence of SEQ ID NO: 371; jj. HCDR1 comprising thesequence of SEQ ID NO: 376, a HCDR2 comprising the sequence of SEQ IDNO: 377, a HCDR3 comprising the sequence of SEQ ID NO: 378, a LCDR1comprising the sequence of SEQ ID NO: 379, a LCDR2 comprising thesequence of SEQ ID NO: 380, a LCDR3 comprising the sequence of SEQ IDNO: 381; kk. HCDR1 comprising the sequence of SEQ ID NO: 386, a HCDR2comprising the sequence of SEQ ID NO: 387, a HCDR3 comprising thesequence of SEQ ID NO: 388, a LCDR1 comprising the sequence of SEQ IDNO: 389, a LCDR2 comprising the sequence of SEQ ID NO: 390, a LCDR3comprising the sequence of SEQ ID NO: 391; ll. HCDR1 comprising thesequence of SEQ ID NO: 396, a HCDR2 comprising the sequence of SEQ IDNO: 397, a HCDR3 comprising the sequence of SEQ ID NO: 398, a LCDR1comprising the sequence of SEQ ID NO: 399, a LCDR2 comprising thesequence of SEQ ID NO: 400, a LCDR3 comprising the sequence of SEQ IDNO: 401; mm. HCDR1 comprising the sequence of SEQ ID NO: 406, a HCDR2comprising the sequence of SEQ ID NO: 407, a HCDR3 comprising thesequence of SEQ ID NO: 408, a LCDR1 comprising the sequence of SEQ IDNO: 409, a LCDR2 comprising the sequence of SEQ ID NO: 410, a LCDR3comprising the sequence of SEQ ID NO: 411; nn. HCDR1 comprising thesequence of SEQ ID NO: 416, a HCDR2 comprising the sequence of SEQ IDNO: 417, a HCDR3 comprising the sequence of SEQ ID NO: 418, a LCDR1comprising the sequence of SEQ ID NO: 419, a LCDR2 comprising thesequence of SEQ ID NO: 420, a LCDR3 comprising the sequence of SEQ IDNO: 421; oo. HCDR1 comprising the sequence of SEQ ID NO: 426, a HCDR2comprising the sequence of SEQ ID NO: 427, a HCDR3 comprising thesequence of SEQ ID NO: 428, a LCDR1 comprising the sequence of SEQ IDNO: 429, a LCDR2 comprising the sequence of SEQ ID NO: 430, a LCDR3comprising the sequence of SEQ ID NO:
 431. 36. The antibody or anantigen-binding fragment thereof of claim 35, wherein said antibody orantigen-binding domain comprises a heavy chain variable region comprisesa sequence selected from the group consisting of SEQ ID NO: 7, 17, 27,37, 47, 57, 61, 71, 81, 91, 101, 111, 142, 152, 162, 172, 182, 192, 202,212, 222, 232, 242, 252, 262, 272, 282, 292, 302, 312, 322, 332, 342,352, 362, 372, 382, 392, 402, 412, 422 and 432, or a homologous sequencethereof having at least 80% sequence identity.
 37. The antibody or anantigen-binding fragment thereof of claim 35, wherein said antibody orantigen-binding domain comprises a light chain variable region comprisesa sequence selected from the group consisting of SEQ ID NO: 8, 18, 28,38, 48, 58, 62, 72, 82, 92, 102, 112, 143, 153, 163, 173, 183, 193, 203,213, 223, 233, 243, 253, 263, 273, 283, 293, 303, 313, 323, 333, 343,353, 363, 373, 383, 393, 403, 413, 423 and 433, or a homologous sequencethereof having at least 80% sequence identity.
 38. The antibody or anantigen-binding fragment thereof of claim 35, wherein said antibody orantigen-binding domain comprises a pair of heavy chain variable regionand light chain variable region sequences selected from the groupconsisting of: SEQ ID NOs: 7/8, 17/18, 27/28, 37/38, 47/48, 57/58,61/62, 71/72, 81/82, 91/92, 101/102, 111/112, and 142/143, 152/153,162/163, 172/173, 182/183, 192/193, 202/203, 212/213, 222/223, 232/233,242/243, 252/253, 262/263, 272/273, 282/283, 292/293, 302/303, 312/313,322/323, 332/333, 342/343, 352/353, 362/363, 372/373, 382/383, 392/393,402/403, 412/413, 422/423 and 432/433, or a pair of homologous sequencesthereof having at least 80% sequence identity yet retaining specificbinding affinity to RBD of spike protein of SARS-CoV-2.
 39. The antibodyor an antigen-binding fragment thereof of claim 35, wherein saidantibody or antigen-binding domain comprises at least one amino acidsubsequent substitutions in said antigen-binding domain.
 40. Theantibody or an antigen-binding fragment thereof of claim 39, whereinsaid subsequent substitution comprises substituting a cysteine residueto a non-cysteine residue.
 41. The antibody or an antigen-bindingfragment thereof of claim 40, wherein said cysteine residue issubstituted with a serine residue.
 42. The antibody or anantigen-binding fragment thereof of claim 35, wherein said antibody orantigen-binding domain further comprises an immunoglobulin constantregion of human IgG.
 43. The antibody or an antigen-binding fragmentthereof of claim 42, wherein said antibody or antigen-binding domaincomprises at least one amino acid substitutions in said human IgGconstant domain, a light chain of said modified antibody, a heavy chainof said antibody, or a combination thereof.
 44. The antibody or anantigen-binding fragment thereof of claim 43, wherein said antibody orantigen-binding domain comprises at least one amino acid substitutionsin said human IgG constant domain resulting in reduced effectorfunctions relative to a wildtype Fc.
 45. The antibody or anantigen-binding fragment thereof of claim 44, wherein said antibody orantigen-binding domain comprises one or more amino acid substitution(s)at a position selected from the group consisting of: 220, 226, 229, 233,234, 235, 236, 237, 238, 267, 268, 269, 270, 297, 309, 318, 320, 322,325, 328, 329, 330, and 331 of the Fc region, wherein the numbering ofthe residues in the Fc region is that of the EU index as in Kabat. 46.The antibody or an antigen-binding fragment thereof of claim 45, whereinsaid antibody or antigen-binding domain comprises one or more amino acidsubstitution(s) selected from the group consisting of 220S, 226S, 228P,229S, 233P, 234V, 234G, 234A, 234F, 234A, 235A, 235G, 235E, 236E, 236R,237A, 237K, 238S, 267R, 268A, 268Q, 269R, 297A, 297Q, 297G, 309L, 318A,322A, 325L, 328R, 330S, 331S and any combination thereof.
 47. Theantibody or an antigen-binding fragment thereof of claim 45, whereinsaid antibody or antigen-binding domain comprises a combination ofmutations selected from the group consisting of: a) K322A, L234A, andL235A; b) P331S, L234F, and L235E; c) L234A and L235A; c) N297A; d)N297Q; e) N297G; f) L235E; g) L234A and L235A (IgG1); h) F234A and L235A(IgG4); i) H268Q, V309L, A330S and P331S (IgG2); j) V234A, G237A, P238S,H268A, V309L, A330S and P331S (IgG2).
 48. The antibody or anantigen-binding fragment thereof of claim 43, wherein said antibody orantigen-binding domain comprises one or more amino acid residuemodifications or substitutions resulting in improved binding affinity toneonatal Fc receptor (FcRn) at pH 6.0 while retaining minimal binding atpH 7.4, or increased serum half life of the antibody.
 49. The antibodyor an antigen-binding fragment thereof of claim 48, wherein saidantibody or antigen-binding domain comprises one or more amino acidsubstitution(s) at a position selected from the group consisting of:234, 235, 238, 250, 252, 254, 256; 259; 272, 305, 307, 308, 311, 312,322, 328, 331, 378, 380, 382, 428, 432, 433, 434, 435, 436 and 437, allpositions by EU numbering.
 50. The antibody or an antigen-bindingfragment thereof of claim 49, wherein said antibody or antigen-bindingdomain comprises one or more amino acid substitution(s) selected fromthe group consisting of 234F, 235Q, 238D, 250Q, 252T, 252Y, 254T, 256E,259I, 272A, 305A, 307A, 308F, 311A, 322Q, 328E, 331S, 380A, 428L, 432C,433K, 433S, 434S, 434Y, 434F, 434W, 434A, 435H, 436L, 437C and anycombination thereof.
 51. The antibody or an antigen-binding fragmentthereof of claim 50, wherein said antibody or antigen-binding domain hasincreased serum half-life or improved pH-dependent binding to FcRn andcomprises a combination of mutations selected from the group consistingof: a) M428L and N434S; b) P238D and L328E; c) M252Y, S254T and T256E;d) L234F, L235Q, K322Q, M252T, S254T and T256E; e) M428L, V259I andV308F; f) H433K and N434Y; g) H433K and N434F; h) T250Q and M428L; i)T307A, E380A and N434A; and j) 432C, 433S, 434W, 435H, 436L, and 437C.52. The antibody or an antigen-binding fragment thereof of claim 34,wherein said modified antibody or said antigen-binding fragment thereofis a diabody, a Fab, a Fab′, a F(ab′)2, a Fd, an Fv fragment, adisulfide stabilized Fv fragment, a (dsFv)2, a bispecific dsFv, adisulfide stabilized diabody, a single-chain antibody molecule, an scFvdimer, a bispecific scFv dimer, or a multispecific antibody.
 53. Theantibody or an antigen-binding fragment thereof of claim 35, which islinked to one or more conjugate moieties.
 54. A bispecific antibodycomprising one or more of the antigen-binding fragment of claim
 35. 55.An isolated polynucleotide encoding the antibody or antigen bindingfragment of claim
 35. 56. A vector comprising the isolatedpolynucleotide of claim
 55. 57. A host cell comprising the vector ofclaim
 56. 58. A pharmaceutical composition comprising at least one saidantibody or an antigen-binding fragment thereof of claim 35, at leastone nucleic acid encoding said modified antibody or said antigen-bindingfragment thereof, or a combination thereof, and one or morepharmaceutically acceptable carriers.
 59. A method for treating orpreventing a disease in a subject in need thereof, said methodcomprising administering an effective dosage of said pharmaceuticalcomposition of claim 58 to said subject.
 60. The method of claim 59,wherein the disease is associated with SARs-CoV-2 infection.
 61. Themethod of claim 59, wherein said pharmaceutical composition isadministered to said subject having no symptoms or free from knowninfections of said SARS-CoV-2, prior to said subject being infected withsaid SARS-CoV-2, prior to said subject exhibiting any symptoms of theinfection of said SARS-CoV-2, or a combination thereof.
 62. The methodof claims 59, wherein said pharmaceutical composition is administered tosaid subject via intravenous injection (IV), intramuscular injection(IM), subcutaneous (SC) injection, or a combination thereof.
 63. Themethod of claim 59, wherein said subject is a patient of age 60, 70 or80 years old or older.
 64. The method of claim 59, wherein saideffective dosage is determined by a dosing process that comprisesdetermining concentration progression data based on calculated ormeasured pharmacokinetics (PK), testing plasma concentrations over atesting period of time, predicted plasma concentrations over aprediction period of time, or a combination thereof, of said antibody orsaid antigen-binding fragment thereof, and producing said effectivedosage based on said concentration progression data.
 65. The method ofclaim 59, further comprising administering a pharmaceutically effectiveamount of one or more bioactive agents to said subject simultaneously orsequentially with said pharmaceutical composition, wherein saidbioactive agent comprises a therapeutic agent or a prophylactic agentselected from an anti-viral agent, an antiviral peptide, an anti-viralantibody, an anti-viral compound, an anti-viral cytokine, an anti-viraloligonucleotide, an RNA dependent RNA polymerase inhibitor, anon-nucleoside reverse transcriptase inhibitor (NNRTI), nucleosidereverse transcriptase inhibitor (NRTI), purine nucleoside, antiviralinterferon, adamantine antiviral compound, remdesivir, chloroquine,hydroxychloroquine, lopinavir, ritonavir, APN01, favilavir, mesalazine,toremifene, eplerenone, paroxetine, sirolimus, dactinomycin, irbesartan,emodin, mercaptopurine, melatonin, quinacrine, carvedilol, colchicine,camphor, equilin, oxymetholone, nafamosta, camostat, baricitinib,darunavir, ribavirin, galidesivir, BCX-4430, Arbidol, nitazoxanide, oneor more derivatives thereof, or any combination thereof.